Aralkyl and aralkylidene heterocyclic lactams and imides

ABSTRACT

The present invention relates to compounds of the formula  
                 
 
     wherein R 1 , R 2 , R 3 , X, Y and the dashed line are defined as in the specification, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. These compounds are useful as psychotherapeutic agents.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to novel aralkyl and aralkylideneheterocyclic lactams and imides, to intermediates for their preparation,to pharmaceutical compositions containing them and to their medicinaluse. The compounds of the present invention include selective agonistsand antagonists of serotonin 1 (5-HT₁) receptors, specifically, of oneor both of the 5-HT_(1A) and 5-HT_(1D) receptors. They are useful intreating or preventing migraine, depression and other disorders forwhich a 5-HT₁ agonist or antagonist is indicated.

[0002] European Patent Publication 434,561, published on Jun. 26, 1991,refers to 7-alkyl, alkoxy, and hydroxysubstituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compoundsare referred to as 5-HT₁ agonists and antagonists useful for thetreatment of migraine, depression, anxiety, schizophrenia, stress andpain.

[0003] European Patent Publication 343,050, published on Nov. 23, 1989,refers to 7-unsubstituted, halogenated, and methoxysubstituted-1-(4-substituted-1-piperazinyl)-naphthalenes as useful5-HT_(1A) ligand therapeutics.

[0004] PCT publication WO 94/21619, published Sep. 29, 1994, refers tonaphthalene derivatives as 5-HT₁ agonists and antagonists.

[0005] PCT publication WO 96/00720, published Jan. 11, 1996, refers tonaphthyl ethers as useful 5-HT₁ agonists and antagonists.

[0006] European Patent Publication 701,819, published Mar. 20, 1996,refers to the use of 5-HT₁ agonists and antagonists in combination witha 5-HT re-uptake inhibitor.

[0007] Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthaleneas a useful 5-HT₁ ligand in their article “5-HT_(1D) SerotoninReceptors”, Clinical Drug Res. Dev., 22, 25-36 (1991).

[0008] Glennon's article “Serotonin Receptors: Clinical Implications”,Neuroscience and Behavioral Reviews, 14, 3547 (1990), refers to thepharmacological effects associated with serotonin receptors includingappetite suppression, thermoregulation, cardiovascular/hypotensiveeffects, sleep, psychosis, anxiety, depression, nausea, emesis,Alzheimer's disease, Parkinson's disease and Huntington's disease.

[0009] World Patent Application WO 95/31988, published Nov. 30, 1995,refers to the use of a 5-HT _(1D)antagonist in combination with a5-HT_(1A) antagonist to treat CNS disorders such as depression,generalized anxiety, panic disorder, agoraphobia, social phobias,obsessive-compulsive disorder, post-traumatic stress disorder, memorydisorders, anorexia nervosa and bulimia nervosa, Parkinson's disease,tardive dyskinesias, endocrine disorders such as hyperprolactinaemia,vasospasm (particularly in the cerebral vasculature) and hypertension,disorders of the gastrointestinal tract where changes in motility andsecretion are involved, as well as sexual dysfunction.

[0010] G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), havestated that administration of agonists selective for 5-HT_(1A) receptorsor for both 5-HT_(1A) and 5-HT_(1D) receptors might represent a greatimprovement in the treatment of human cerebellar ataxias, a multifacetedsyndrome for which no established therapy is available.

[0011] European Patent Publication 666,261, published Aug. 9, 1995refers to thiazine and thiomorpholine derivatives which are claimed tobe useful for the treatment of cataracts.

SUMMARY OF THE INVENTION

[0012] The present invention relates to compounds of the formula

[0013] wherein R¹ is a group of the formula G¹, G², G³, G⁴, G⁵, G⁶ or G⁷depicted below,

[0014] a is zero to eight;

[0015] each R¹³ is, independently, (C₁-C₄)alkyl or a (C₁-C₄)methylenebridge from one of the ring carbons of the piperazine or piperidine ringof G¹ or G², respectively, to the same or another ring carbon or a ringnitrogen of the piperazine or piperidine ring of G¹ or G², respectively,having an available bonding site, or to a ring carbon of R⁶ having anavailable bonding site;

[0016] E is oxygen, sulfur, SO or SO₂;

[0017] X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C₁-C₆)alkyl,hydroxy, trifluoromethyl, (C₁-C₆)alkoxy, —SO,(C₁-C₁)alkyl wherein t iszero one or two, —CO₂R¹⁰ or —CONR¹¹R¹²;

[0018] Y is an optionally substituted (C¹-C₄) heteroalkyl bridge that,together with the atoms to which it is attached, forms a five to sevenmembered heterocycle containing two to four heteroatoms selected fromthe group consisting of 1,3-oxazolidin-4-on-5-yl,1,3-oxazolidin-2,4-dion-5-yl, 4,5-dihydro-1,2-oxazolidin-3-on-4-yl,1,3-thiazolidin-4-on-5-yl,1,3-thiazolidin-2,4-dion-5-yl,1,3-pyrazolidin4-on-5-yl, 1,3-imidazolidin-2,4-dion-5-yl,1,2-pyrazolidin-3-on-4-yl, 1,2-thiazolidin-1,1,3-trion-4-yl,1,2-thiazolidin-3-on-4-yl, tetrahydro-1,2-oxazin-3-on-4-yl,tetrahydro-1,3-oxazin4-on-5-yl, tetrahydro-1,3-oxazin-2,4-dion-5-yl,morpholin-3-on-2-yl, morpholin-3,5-dion-2-yl,2,3-dihydro-1,4-oxazin-3-on-2-yl, tetrahydro-1,3-thiazin-4-on-5-yl,tetrahydro-1,3-thiazin-2,4-dion-5-yl, tetrahydro-1,2-thiazin-3-on-4-yl,thiomorpholin-3-on-2-yl, thiomorpholin-3,5-dion-2-yl,2,3-dihydro-1,4-thiazin-3-on-2-yl, hexahydro-1,2-diazin-3-on-4-yl,4,5-dihydro-2H-pyridazin-3-on-4-yl, hexahydro-1,3-diazin-4-on-5-yl,hexahydro-1,3-diazin-2,4-dion-5-yl, piperazin-2-on-3-yl,piperazin-2,6-dion-3-yl, tetrahydro-1,3,4-thiadiazin-5-on-6-yl,5,6-dihydro-1,3,4-thiadiazin-5-on-6-yl, 1,3,4-oxadiazin-5-on-6-yl,5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl,tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-yl,tetrahydro-1,2,4-oxadiazin-5-on-6-yl,5,6-dihydro-1-2,4-oxadiazin-5-on-6-yl, 1,2,4-oxadiazin-3,5-dion-6-yl,1,2,4-trazin-6-on-5-yl, hexahydro-1,2-oxazepin-3-on-2-yl,hexahydro-1,3-oxazepin4-on-5-yl, hexahydro-1,4-oxazepin-3-on-2-yl,hexahydro-1,4-oxazepin-3,5-dion-2-yl,hexahydro-1,4-oxazepin-3,5-dion-6-yl,2,3,5,6-tetrahydro-1-4-oxazepin-5,7-dion-6-yl,hexahydro-1,4-oxazepin-5-on-6-yl, hexahydro-1,3-oxazepin-2,4-dion-5-yl,hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro-1,4-thiazepin-3-on-2-yl,2,3,4,5-tetrahydro-1,4-thiazepin-3-on-2-yl,hexahydro-1,4-thiazepin-3,5-dion-2-yl,hexahydro-1,4-thiazepin-3,5-dion-6-yl,2,3,6,7-tetrahydro-1,4-thiazepin-5-on-6-yl,6,7-dihydro-1,4-thiazepin-5-on-6-yl,hexahydro-1,3-thiazepin-2,4-dion-5-yl, hexahydro-1,2-diazepin-3-on-4-yl,hexahydro-1,3-diazepin-2,4-dion-5-yl, hexahydro-1,4-diazepin-2-on-3-yl,hexahydro-1,4-diazepin-5-on-6-yl, hexahydro-1,4-diazepin-5,7-dion-6-yl,hexahydro-1,3,5-thiadiazepin-3-on-7-yl,4,5,6,7-tetrahydro-1-3,5-thiadiazepin-6-on-7-yl, and2,3,5,6-tetrahydro-1,2,4-triazepin-3,5-dion-7-yl; wherein thesubstituents on any of the carbon atoms capable of supporting anadditional bond, of said (C₁-C₄) heteroalkyl bridge, are chloro, fluoro,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl or cyano; wherein thesubstituents on any of the nitrogen atoms capable of supporting anadditional bond, of said (C₁-C₄) heteroalkyl bridge, are (C₁-C₆)alkyl ortrifluoromethyl;

[0019] R² is hydrogen, (C₁-C₄)alkyl, phenyl or naphthyl, wherein saidphenyl or naphthyl may optionally be substituted with one or moresubstituents independently selected from chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—SO_(k)(C₁-C₆)alkyl wherein k is zero, one or two,

[0020] R³ is —(CH₂)_(m)B, wherein m is zero, one, two or three and B ishydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl groupcontaining from one to four heteroatoms in the ring, and wherein each ofthe foregoing phenyl, naphthyl and heteroaryl groups may optionally besubstituted with one or more substituents independently selected fromchloro, fluoro, bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy-(C₁-C₆)alkyl-, trifluoromethyl, trifluoromethoxy, cyano,hydroxy, —COOH and —SO_(n)(C₁-C₆)alkyl wherein n is zero, one or two;

[0021] R⁶ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally substituted with (C₁-C₆)alkoxy or one to threefluorine atoms, or [(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl,naphthyl, or heteroaryl-(CH₂)_(q)—, wherein the heteroaryl moiety isselected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—SO_(g)(C₁-C₆)alkyl, wherein g is zero, one or two;

[0022] R⁷ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, [(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl,naphthyl, or heteroaryl-(CH₂)_(r)—, wherein the heteroaryl moiety isselected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, —C(═O)—(C₁-C₆)alkyl, cyanoand —SO,(C₁-C₆)alkyl, wherein j is zero, one or two;

[0023] or R⁶ and R⁷ taken together form a 2 to 4 carbon chain;

[0024] R⁸ is hydrogen or (C₁-C₃)alkyl;

[0025] R⁹ is hydrogen or (C₁-C₆)alkyl;

[0026] or R⁶ and R⁹, together with the nitrogen atom to which they areattached, form a 5 to 7 membered heteroalkyl ring that may contain fromzero to four heteroatoms selected from nitrogen, sulfur and oxygen;

[0027] and p is one, two, or three;

[0028] each of R¹⁰, R¹¹ and R¹² is selected, independently, from theradicals set forth in the definition of R²; or R¹¹ and R¹², togetherwith the nitrogen to which they are attached, form a 5 to 7 memberedheteroalkyl ring that may contain from zero to four heteroatoms selectedfrom nitrogen, sulfur and oxygen; and

[0029] the broken lines indicate optional double bonds, with the provisothat when the broken line in G² is a double bond that R⁸ is absent;

[0030] or a pharmaceutically acceptable salt thereof.

[0031] The following are more specific embodiments of groups G¹ and G².

[0032] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula I. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0033] The invention also relates to base addition salts of formula I.The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of formula Ithat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

[0034] The compounds of this invention include all stereoisomers (e.g.,cis and trans isomers) and all optical isomers of compounds of theformula I (e.g., R and S enantiomers), as well as racemic,diastereomeric and other mixtures of such isomers.

[0035] The compounds of this invention may contain olefin-like doublebonds. When such bonds are present, the compounds of the invention existas cis and trans configurations and as mixtures thereof.

[0036] Unless otherwise indicated, the alkyl and alkenyl groups referredto herein, as well as the alkyl moieties of other groups referred toherein (e.g., alkoxy), may be linear or branched, and they may also becyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or belinear or branched and contain cyclic moieties. Unless otherwiseindicated, halogen includes fluorine, chlorine, bromine, and iodine.

[0037] Preferred compounds of the formula I include those wherein R¹ is

[0038] R⁶ is methyl and R² is hydrogen.

[0039] Preferred compounds of the formula I also include those whereinY, together with the atoms to which it is attached, forms an optionallysubstituted five to seven membered heterocycle selected from 1,3thiazolidin-2,4-dion-5-yl, 1,3 imidazolidin-2,4-dion-5-yl,thiomorpholin-3-on-2-yl or morpholin-3-on-2-yl.

[0040] Preferred compounds of the formula I also include those whereinR³ is optionally substituted phenyl or —(CH₂)-optionally substitutedphenyl.

[0041] Examples of specific preferred compounds of the formula I are thefollowing:

[0042]3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-imidazolidine-2,4-dione;

[0043]3-(4-chlorobenzyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-imidazolidine-2,4-dione;

[0044]3-(4-chlorobenzyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dione;

[0045]4-benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0046]4-(3,4-dichlorobenzyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0047]3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dione;

[0048]3-(4-trifluoromethylphenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dione;

[0049]2-[2-(4-methylpiperazin-1-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;

[0050] 2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0051]4-(3,4-dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0052]4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-morpholin-3-one;

[0053]4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0054]4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzyl]-thiomorpholin-3-one;

[0055]4-methyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;and

[0056]4-(3,4-dichlorophenyl)-2-(2-piperazin-1-ylbenzylidene)-thiomorpholin-3-one.

[0057]4-Benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,1-dioxothiomorpholin-3-one;

[0058]4-(3,4-Dichlorophenyl)-2-[3-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0059]4-(3,4-Dichlorophenyl)-2-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0060]4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-5-trifluoromethyl-benzylidene]-thiomorpholin-3-one;

[0061] 4-(3,4-Dichlorophenyl)-2-{2-[4-(2-me thoxyethyl)piperazin-1-yl]-benzylidene}-thiomorpholin-3-one;

[0062]4-(3,4-Dichlorophenyl)-2-[2-(4-isopropylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0063] 4-(3,4-Dichlorophenyl)-2-[2-(4-ethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0064]4-(4-Chlorophenyl)-2-[2-(4-methyipiperazin-1-yl)-benzylidene)-thiomorpholin-3-one;

[0065]4-(3-Chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0066]2-[2-Chloro-6-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;

[0067]4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-4-trifluoromethyl-benzylidene)-thiomorpholin-3-one;

[0068]4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-oxo-thiomorpholin-3-one;

[0069]4-(3,4-Dichlorophenyl)-2-(5-fluoro-2-piperazin-1-yl-benzylidene)-thiomorpholin-3-one;

[0070]4-(3,4-Dichlorophenyl)-2-[3,6-difluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0071]4-(3,4-Dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0072]4-Phenyl-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0073]2-[5-Fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-4-phenyl-thiomorpholin-3-one;

[0074]4-Benzo[1,3]dioxol-5-yl-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0075]2-[2-(4-tert-Butylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;

[0076]3-(3,4-Dichlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidin4-one;

[0077]3-[4-(3,4-Dichlorophenyl)-3-oxo-thiomorpholin-2-ylidenemethyl]-6-dimethylamino-2-(4-methylpiperazin-1-yl)-benzonitrile;

[0078]5-[2-(4-Methylpiperazin-1-yl)-benzylidene]-2-phenylthiazolidin-4-one;

[0079]4-(3,4-Dichlorophenyl)-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0080]4-(3,4-Dichlorophenyl)-2-[5-methyl-2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0081]2-[4-Chloro-2-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;

[0082]4-(3,4-Difluorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0083]4-(2,4-Difluorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0084]2-[4-Bromo-2-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;

[0085]4-(3,4-Dichlorophenyl)-2-[2-(1-methylpyrrolidin-2-ylmethoxy)-benzylidene]-thiomorphoilin-3-one;

[0086]4-(3,5-Dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0087]4-(3,4-Difluorophenyl)-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0088]4-(3,4-Dichlorophenyl)-2-[2-(octahydropyrido[1,2-a]pyrazin-2-yl)-benzylidene]-thiomorpholin-3-one;

[0089]2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-pyridin-3-yl-thiomorpholin-3-one;

[0090]2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,4-difluorophenyl)thiomorpholin-3-one;

[0091]2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,5-dichlorophenyl)thiomorpholin-3-one;

[0092]4-(3,4-Difluorophenyl)-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0093]4-(3,5-Dichlorophenyl)-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0094]4-(3,4-Dichlorophenyl)-2-[2-(3-methylaminopyrrolidin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0095]4-(3,4-Difluorophenyl)-2-[2-(2,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0096]4-Benzo[1,3]dioxol-5-yl-2-[2-(4-cyclopropylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0097]2-[2-(3,5-Dimethylpiperazin-1-yl)-benzylidene]4-(4-fluorophenyl)-thiomorpholin-3-one;

[0098]4-Benzo[1,3]dioxol-5-yl-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0099]2-[2-(3,5-Dimethylpiperazin-1-yl)-benzylidene]4-phenylthiomorpholin-3-one;

[0100]4-(3,4-Dichlorophenyl)-2-(2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0101]4-(3,4-Dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-1-yl)-benzylidene)-thiomorpholin-3-one;

[0102]4-(3,4-Dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0103]4-(3,4-Dichlorophenyl)-2-[2-(4-methyl-[1,4]diazepan-1-yl)-benzylidene]-thiomorpholin-3-one;

[0104]4-(3,4-Dichlorophenyl)-2-(2-(2,4,6-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;and

[0105]2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;

[0106] and the pharmaceutically acceptable salts of such compounds.

[0107] Other compounds of formula I include the following:

[0108]5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dione;

[0109]2-[2,4-dibromo-6-(4-methylpiperazin-1-yl)-benzylidene]4-(3,4-dichlorophenyl)-thiomorpholin-3-one;

[0110]4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-[1,4]oxazepan-3-one;

[0111]4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-[1,4,5]oxadiazepan-3-one;

[0112]4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-[1,4]thiazepan-3-one;

[0113]4-(3,4-dichlorophenyl)-2-{2-[(2-dimethylaminoethyl)-methyl-amino]-benzylidene}-thiomorpholin-3-one;

[0114]4-(3,4-dichlorophenyl)-2-[2-(1-methylpiperidin-4-yl)-benzylidene]-thiomorpholin-3-one;

[0115]4-(3,4-dichlorophenyl)-2-[2-(1,4-dimethylpiperidin-4-yl)-benzylidene]-thiomorpholin-3-one;

[0116]4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholine-3,5-dione;

[0117]4-(3,4-dichlorophenyl)-2-[2-(2-dimethylaminoethoxy)-benzylidene]-thiomorpholin-3-one;

[0118]4-(3,4-dichlorophenyl)-2-[2-(4-isopropylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0119]4-(3,4-dichlorophenyl)-2-[2-(1-methylpyrrolidin-3-ylmethyl)-benzylidene]-thiomorpholin-3-one;

[0120]4-(3,4-dichlorophenyl)-2-{2-[methyl-(1-methylpyrrolidin-2-ylmethyl)-amino]-benzylidene}-thiomorpholin-3-one;

[0121]4-(3,4-dichlorophenyl)-2-[2-(1-methylpyrrolidin-2-ylmethoxy)-benzylidene]-thiomorpholin-3-one;

[0122]4-(3,4-dichlorophenyl)-2-{2-[2-(1-methylpyrrolidin-2-yl)-ethyl]-benzylidene}-thiomorpholin-3-one;

[0123]1-(3,4-dichlorophenyl)-4-methyl-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperazin-2-one;

[0124]4-methyl-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-(4-trifluoromethylphenyl)-piperazin-2-one;

[0125]1-(4-chlorophenyl)-4-methyl-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperazin-2-one;

[0126] 2-[2-(4-methylpiperazin-1-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-morpholin-3-one;

[0127]2-[4-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;

[0128]2-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;

[0129]2-{1-[2-(4-methylpiperazin-1-yl)-phenyl]-ethylidene}4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;

[0130] 2-[2-(4-methylpiperazin-1-yl)-benzyl]4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;

[0131]4-(4-chlorophenyl)-6-methyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;

[0132]3-(4-chlorophenyl)-2,2-dimethyl-5-(2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidin-4-one;

[0133]4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-[1,4]oxazepan-3-one;

[0134]4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-4H-[1,4]thiazin3-one;

[0135]1-(4-chlorophenyl)-4,6,6-trimethyl-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperazin-2-one;

[0136]1-(4-chlorophenyl)-4-methyl-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperazin-2-one;

[0137]4-(4-chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-morpholin-3-one;

[0138]3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-oxazolidin-4-one;

[0139]3-(4-chlorophenyl)-2,2-dimethyl-5-[2-(4-methyipiperazin-1-yl)-benzylidene]-imidazolidin4-one;and

[0140]3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-imidazolidin-4-one.

[0141] The present invention also relates to intermediates of theformula

[0142] wherein R¹-R³, R⁶-R¹³, G⁷- G⁵, X, B, E, Y, Z, g, j, k, m, n, p,q, r and t are as defined above.

[0143] Examples of specific preferred compounds of formula V are thefollowing:

[0144]4-benzyl-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}thiomorpholin-3-one;

[0145]4-(3,4-dichlorobenzyl)-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}-thiomorpholin-3-one;

[0146]2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;

[0147]2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}thiomorpholin-3-one;

[0148]4-(3,4-dichlorophenyl)-2-{[2-fluoro-6-(4-methylpiperazin-1-yl)-phenyl]-hydroxymethyl}-thiomorpholin-3-one;

[0149]4-(3,4-dichlorophenyl)-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]-methyl}-morpholin-3-one;

[0150]2-{[2,4-dibromo-6-(4-methylpiperazin-1-yl)-phenyl]-hydroxymethyl}-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;and

[0151]4-(3,4-dichlorophenyl)-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]-methyl}-thiomorpholin-3-one.

[0152] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a disorder or condition selectedfrom hypertension, depression, generalized anxiety disorder, phobias(e.g., agoraphobia, social phobia and simple phobias), posttraumaticstress syndrome, avoidant personality disorder, premature ejaculation,eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies (e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g, dementia, amnestic disorders, andage-related cognitive decline (ARCD)), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders (involving changes in motility andsecretion), negative symptoms of schizophrenia, premenstrual syndrome,Fibromyalgia Syndrome, stress incontinence, Tourette syndrome,trichotillomania, kleptomania, male impotence, cancer (e.g. small celllung carcinoma), chronic paroxysmal hemicrania and headache (associatedwith vascular disorders) in a mammal, preferably a human, comprising anamount of a compound of the formula I or a pharmaceutically acceptablesalt thereof effective in treating or preventing such disorder orcondition and a pharmaceutically acceptable carrier.

[0153] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a disorder or condition that canbe treated or prevented by enhancing serotonergic neurotransmission in amammal, preferably a human, comprising an amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof, effective intreating or preventing such disorder or condition and a pharmaceuticallyacceptable carrier. Examples of such disorders and conditions are thoseenumerated in the preceding paragraph.

[0154] The present invention also relates to a method for treating orpreventing a disorder or condition selected from hypertension,depression (e.g., depression in cancer patients, depression inParkinson's patients, Postmyocardial Infarction depression, SubsyndromalSymptomatic depression, depression in infertile women, pediatricdepression, major depression, single episode depression, recurrentdepression, child abuse induced depression, and post partum depression),generalized anxiety disorder, phobias (e.g., agoraphobia, social phobiaand simple phobias), posttraumatic stress syndrome, avoidant personalitydisorder, premature ejaculation, eating disorders (e.g., anorexianervosa and bulimia nervosa), obesity, chemical dependencies (e.g.,addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine andbenzodiazepines), cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders (e.g.,dementia, amnestic disorders, and age-related cognitive decline (ARCD)),Parkinson's diseases (eg., dementia in Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias), endocrinedisorders (e.g., hyperprolactinaemia), vasospasm (particularly in thecerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders (involving changes in motility and secretion), negativesymptoms of schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome,stress incontinence, Tourette syndrome, trichotillomania, kleptomania,male impotence, cancer, (e.g. small cell lung carcinoma), chronicparoxysmal hemicrania and headache (associated with vascular disorders)in a mammal, preferably a human, comprising administering to a mammal inneed of such treatment or prevention an amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof, that iseffective in treating or preventing such disorder or condition.

[0155] The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal in need of such treatment orprevention an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingor preventing such disorder or condition.

[0156] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a disorder or condition selectedfrom hypertension, depression (e.g., depression in cancer patients,depression in Parkinson's patients, Postmyocardial Infarctiondepression, Subsyndromal Symptomatic depression, depression in infertilewomen, pediatric depression, major depression, single episodedepression, recurrent depression, child abuse induced depression, andpost partum depression), generalized anxiety disorder, phobias (e.g.,agoraphobia, social phobia and simple phobias), posttraumatic stresssyndrome, avoidant personality disorder, premature ejaculation, eatingdisorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies (e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g., dementia, amnestic disorders,and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders (involving changes in motility andsecretion), negative symptoms of schizophrenia, premenstrual syndrome,Fibromyalgia Syndrome, stress incontinence, Tourette syndrome,trichotillomania, kleptomania, male impotence, cancer (e. small celllung carcinoma), chronic paroxysmal hemicrania and headache (associatedwith vascular disorders) in a mammal, preferably a human, comprising aserotonin receptor antagonizing or agonizing effective amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

[0157] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a disorder or condition that canbe treated or prevented by enhancing serotonergic neurotransmission in amammal, preferably a human, comprising a serotonin receptor antagonizingor agonizing effective amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

[0158] The present invention also relates to a method for treating orpreventing a disorder or condition selected from hypertension,depression (e.g., depression in cancer patients, depression inParkinson's patients, Postmyocardial Infarction depression, SubsyndromalSymptomatic depression, depression in infertile women, pediatricdepression, major depression, single episode depression, recurrentdepression, child abuse induced depression, and post partum depression),generalized anxiety disorder, phobias (e.g., agoraphobia, social phobiaand simple phobias), posttraumatic stress syndrome, avoidant personalitydisorder, sexual dysfunction (e.g., premature ejaculation), eatingdisorders (e.g., anorexia nervosa and bulimia nervosa), obesity,chemical dependencies (e.g., addictions to alcohol, cocaine, heroin,phenolbarbitol, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g., dementia, amnestic disorders,and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g.,dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders (involving changes in motility andsecretion), negative symptoms of schizophrenia, premenstrual syndrome,Fibromyalgia Syndrome, stress incontinence, Tourette syndrome,trichotillomania, kleptomania, male impotence, cancer (e.g., small celllung carcinoma), chronic paroxysmal hemicrania and headache (associatedwith vascular disorders) in a mammal, preferably a human, comprisingadministering to a mammal requiring such treatment or prevention aserotonin receptor antagonizing or agonizing effective amount of acompound of the formula I or a pharmaceutically acceptable salt thereof.

[0159] The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal requiring such treatment orprevention a serotonin receptor antagonizing or agonizing effectiveamount of a compound of the formula I or a pharmaceutically acceptablesalt thereof.

[0160] The present invention relates to a pharmaceutical composition fortreating or preventing a condition or disorder that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,preferably a human, comprising:

[0161] a) a pharmaceutically acceptable carrier;

[0162] b) a compound of the formula I or a pharmaceutically acceptablesalt thereof; and

[0163] c) a 5-HT re-uptake inhibitor, preferably sertraline, or apharmaceutically acceptable salt thereof;

[0164] wherein the amount of the active compounds (i.e., the compound offormula I and the 5-HT re-uptake inhibitor) are such that thecombination is effective in treating or preventing such disorder orcondition.

[0165] The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to a mammal requiring such treatment orprevention:

[0166] a) a compound of the formula I, defined above, or apharmaceutically acceptable salt thereof; and

[0167] b) a 5-HT re-uptake inhibitor, preferably sertraline, or apharmaceutically acceptable salt thereof;

[0168] wherein the amounts of the active compounds (i.e., the compoundof formula I and the 5-HT re-uptake inhibitor) are such that thecombination is effective in treating or preventing such disorder orcondition.

[0169] The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, preferably ahuman, comprising administering to said mammal requiring such treatmentor prevention:

[0170] a) a 5-HT_(1A) antagonist or a pharmaceutically acceptable saltthereof; and

[0171] b) a 5-HT_(1D) antagonist of formula I or a pharmaceuticallyacceptable salt thereof;

[0172] wherein the amounts of each active compound (i.e., the 5-HT_(1A)antagonist and the 5-HT_(1D) antagonist) are such that the combinationis effective in treating or preventing such disorder or condition.

[0173] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a disorder or condition that canbe treated or prevented by enhancing serotonergic neurotransmission in amammal, preferably a human, comprising:

[0174] a) a 5-HT_(1A) antagonist or a pharmaceutically acceptable saltthereof; and

[0175] b) a 5-HT_(1D) antagonist of formula I or a pharmaceuticallyacceptable salt thereof;

[0176] wherein the amounts of each active compound (i.e., the 5-HT_(1A)antagonist and the 5-HT_(1D) antagonist) are such that the combinationis effective in treating or preventing such disorder or condition.

[0177] “Enhanced serotonergic neurotransmission,” as used herein, refersto increasing or improving the neuronal process whereby serotonin isreleased by a pre-synaptic cell upon excitation and crosses the synapseto stimulate or inhibit the post-synaptic cell.

[0178] “Chemical dependency,” as used herein, means an abnormal cravingor desire for, or an addiction to a drug. Such drugs are generallyadministered to the affected individual by any of a variety of means ofadministration, including oral, parenteral, nasal or by inhalation.Examples of chemical dependencies treatable by the methods of thepresent invention are dependencies on alcohol, nicotine, cocaine,heroin, phenolbarbitol, and benzodiazepines (e.g., Valium (trademark)).“Treating a chemical dependency,” as used herein, means reducing oralleviating such dependency.

[0179] Sertraline,(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine,as used herein has the chemical formula C₁₇H₁₇NCl₂ and the followingstructural formula

[0180] Its synthesis is described in U.S. Pat. No. 4,536,518, assignedto Pfizer Inc. Sertraline hydrochloride is useful as an antidepressantand anorectic agent, and is also useful in the treatment of depression,chemical dependencies, anxiety obsessive compulsive disorders, phobias,panic disorder, post traumatic stress disorder, and prematureejaculation.

DETAILED DESCRIPTION OF THE INVENTION

[0181] Compounds of the formula I may be prepared according to thefollowing reaction schemes and discussion. Unless otherwise indicated,R¹ through R³, R⁶ through R¹³, G¹ through G⁷, X, B, E, Y, Z, g, j, k, m,n, p, q, r and t and structural formula I in the reaction schemes anddiscussion that follow are as defined above.

[0182] Scheme 1 illustrates a method of synthesizing compounds of theformula I wherein the dashed line represents a double carbon-carbon bondand R¹ is a group of the formula G¹, G³, G⁴, G⁵, G⁶ or G⁷. Referring toScheme 1, a compound of the formula III, wherein Q is a suitable leavinggroup (e.g., chloro, fluoro, bromo, mesylate, tosylate, etc.), isreacted with a compound of the formula R¹H, wherein H refers to ahydrogen atom on group E or on nitrogen atoms from G¹, G³, G⁵, G⁶ or G⁷and R¹ is a group of the formula G¹, G³, G⁴, G⁵, G⁶ or G⁷ in thepresence of a base, to form the corresponding compound of formula II.This reaction is generally carried out at a temperature from about 0° C.to about 140° C., preferably at about the reflux temperature, in a polarsolvent such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),preferably DMF. Suitable bases include anhydrous sodium carbonate(Na₂CO₃), potassium carbonate (K₂CO₃), sodium hydroxide (NaOH) andpotassium hydroxide (KOH), as well as amines such as pyrrolidine,triethylamine and pyridine. Anhydrous potassium carbonate is preferred.

[0183] Compounds of formula 11 can be converted into compounds of theformula I, wherein R³ is other than hydrogen, by subjecting them to analdol condensation or Wittig reaction. For example, in the case of analdol condensation, a compound of the formula II can be reacted with acompound of the formula

[0184] in the presence of a base, to form an aldol intermediate of theformula

[0185] which may be isolated or converted directly in the same reactionstep to a compound of the formula I by the loss of water. The degree ofcompletion for the conversion of compounds of the formula II to thealdol product of formula I may be assessed using one or more analyticaltechniques, such as thin layer chromatography (tlc) or massspectrometry. In some instances it may be possible or desirable toisolate the intermediate of formula V. In such case, the compound offormula V may be converted into the compound of formula I by theelimination of water using techniques which are familiar to thoseskilled in the art, for example, by heating to the reflux temperature asolution of the compound of formula V in a solvent such as benzene,toluene or xylene, in the presence of a catalytic amount of benzene- orp-toluene-sulfonic acid with provision for the removal of the watergenerated. Such water removal techniques may involve the use ofmolecular sieves or a Dean-Stark trap to isolate the water created as anazeotrope with the solvent.

[0186] The aldol reaction is typically carried out in a polar solventsuch as DMSO, DMF, tetrahydrofuran (THF), methanol or ethanol, at atemperature from about −78° C. to about 80° C. Preferably, this reactionis carried out in THF at about 25° C. Suitable bases for use in thealdol formation step include potassium carbonate (K₂CO₃), sodiumcarbonate (Na₂CO₃), sodium hydride (NaH), sodium methoxide, sodiummethoxide, potassium-tert.-butoxide, lithium diisopropylamide,pyrrolidine and piperidine. Sodium hydride is preferred. Aldolcondensations are described in “Modern Synthetic Reactions,” Herbert O.House, 2d. Edition, W. A. Benjamin, Menlo Park, Calif., 629-682 (1972)and Tetrahedron, 38 (20), 3059 (1982).

[0187] Compounds of the formula I, wherein R³ is other than hydrogen,can also be prepared from compounds of formula II by reaction with acompound of the formula IV, wherein R³ is hydrogen or —(C═O)R¹³, whereinR¹³ is (C₁-C₆)alkyl or trifluoromethyl, followed by removal of the—C(═O)R¹³ group, if present, and reaction with a compound of the formulaR³-L′ wherein L′ is a leaving group and is defined as Q is defined asabove. These reactions can be carried out in a solvent such asdi-(alkyl)ether, THF, DMF, DMA or DMSO, preferably DMF, in the presenceof a base such as potassium carbonate, sodium carbonate, sodium hydride,potassium hydride, sodium hydroxide or potassium hydroxide, preferablysodium hydride Reaction temperatures can range from about 0° C. to about150° C., preferably from about 25° C. to about the reflux temperature ofthe solvent.

[0188] Alternatively, the compound of formula IV can be converted into acompound of the formula I by means of a Wittig olefination, as describedin Helvetica Chimica Acta, 46, 1580 (1963), and depicted below.

[0189] Thus, the compound of formula IV can be converted into thecorresponding bromide of formula XI using standard brominationconditions, followed by treatment with triphenylphosphine in anhydrousTHF to form the intermediate of formula XII. The compound of formula XIIcan then be treated with a base (e.g., aqueous Na₂CO₃) to generate thecorresponding phosphonium ylide, which can then be reacted with theappropriate intermediate of formula II to produce compounds of generalformula I. This transformation is described in A. Maercker, OrganicReactions, 14, 270 (1965).

[0190] Compounds of the formula I wherein the dashed line represents asingle carbon-carbon bond may be prepared by hydrogenating thecorresponding compounds wherein the dashed line represents a doublecarbon-carbon bond, using standard techniques that are well known tothose skilled in the art. For example, reduction of the double bond maybe effected with hydrogen gas (H₂), using catalysts such as palladium oncarbon (Pd/C), palladium on barium sulfate (Pd/BaSO₄), platinum oncarbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson'scatalyst), in an appropriate solvent such as methanol, ethanol, THF,dioxane or ethyl acetate, at a pressure from about 1 to about 5atmospheres and a temperature from about 10° C. to about 60° C., asdescribed in Catalytic Hydrogenation in Organic Synthesis, PaulRylander, Academic Press Inc., San Diego, 31-63 (1979). The followingconditions are preferred: Pd on carbon, methanol at 25° C. and 50 psi ofhydrogen gas pressure. This method also provides for introduction ofhydrogen isotopes (i.e. deuterium, tritium) by replacing ¹H₂ with ²H₂ or³H₂ in the above procedure.

[0191] An alternative procedure employing the use of reagents such asammonium formate and Pd/C in methanol at the reflux temperature under aninert atmosphere (e.g., nitrogen or argon gas) is also effective inreducing the carbon-carbon double bond of compounds of the formula I.Another alternative method involves selective reduction of thecarbon-carbon bond. This can be accomplished using samarium and iodineor samarium iodide (Sml₂) in methanol or ethanol at about roomtemperature, as described by R. Yanada et. al., Synlett., 443-4 (1995).

[0192] The starting materials of the formulas III and IV are eithercommercially available or known in the art. For example, compounds offormula III in which R² is hydrogen are readily available fromcommercial sources or may be prepared using procedures disclosed in thechemical literature. Compounds of the formula III may also be preparedfrom the corresponding carboxylic acids or esters, (i.e., formula III)wherein R²=OH or O-alkyl), which are commercially available. These acidsor esters can be reduced to the corresponding alcohols of formula XIII,depicted below, wherein Q is defined as for formula III, using one ormore of a variety of reducing agents and conditions, depending upon thenature of the substituents Q and X.

[0193] Such reducing agents include sodium borohydride (NaBH₄), sodiumcyanoborohydride (NaCNBH₃), lithium aluminum hydride (LiAIH₄) and boranein THF (BH₃.THF) in solvents such as methanol, ethanol, THF, diethylether and dioxane. Oxidation of the alcohol of formula XIII to thecorresponding aldehyde of formula II may be accomplished using aselective oxidizing agent such as Jones reagent (hydrogen chromate(H₂CrO₄)), pyridinium chlorochromate (PCC) or manganese dioxide (MnO₂).References for such conversions are readily available (e.g., K. B.Wiberg, Oxidation in Organic Chemistry, Part A, Academic Press Inc,N.Y., 69-72 (1965)).

[0194] Compounds of the formula IV are also commercially available orcan be made by methods well know to those of ordinary skill in the art.Examples of sources of the various compounds of formula IV are presentedin Tables 1-3. TABLE 1 5 MEMBERED HETEROCYCLES IV (Y = —E—D—)

Name D E Reference 1,3-oxazolidin-4- CH₂ O DE 2,339,185; Synthesis, 5,426-428 one (1982); US 2,762,815; Arzneim. Forsch., 27, 766-770 (1977).1,3-oxazolidin-2,4- C═O O Parravicini et al., Farmaco Ed.Sci., dione 31,49-57 (1976); Kricheldorf, Makromol. Chem., 176, 57-74 (1975).4,5-dihydro-1,2- O CH₂ J. Korean Chem. Soc., 36(3), oxazolidin-3-one453-459 (1992). 1,3-thiazolidin-4- CH₂ S EP 626,377; Hansen, Tet. Lett.,35, one (38), 6971-6974 (1994). 1,3-thiazolidin-2,4- C═O S Markley,J.A.C.S., 52, 2137-2140 dione (1930); Dains, J.A.C.S., 43, 615 (1921);Barbry et al., J. Chem. Soc. Perkin Trans. 2, (1), 133-140 (1990);Hansen et al., Tetrahedron Lett., 35, (38), 6971-6974 (1994).1,3-imidazolidin-4- CH₂ NH Fitzi, Angew. Chem, Int. Ed. Eng., one 25,345 (1986); J.Het.Chem., 18(5), 963 (1981); Heterocycles, 20(8), 1615(1983). 1,3-imidazolidin- C═O NH Ware, Chem. Rev., 46, 403-470 2,4-dione(1950); Freter et al., Justus Liebigs Ann. Chem., 607, 174-184 (1957).1,2-pyrazolidin-3- NH CH₂ Japanese Pat. 1,056,161; J.O.C., 40, one 3510(1975); Org.Synth., 48, 8 (1968). 1,2-thiazolidin- SO₂ CH₂ Rasmussen, etal., Chem. Reviews, 1,1,3-trione 76, 389 (1976). 1,2-thiazolidin-3- SCH₂ Luettringhaus et al., Justus Liebigs one Annal. Chem., 679, 123-135(1964); Ibid, Angew. Chem., 76, 51 (1964).

[0195] TABLE 2 6 MEMBERED HETEROCYCLES IV (Y = —F—G—K—)

Name F G K Reference tetrahydro-1,2- CH₂ CH₂ O Khomutov et al., Bull.Acad. oxazin-3-one Sci. USSR Div. Chem. Sci., 1006-1008 (1962); Nally etal., Tet. Lett., 26, 4107, (1985). tetrahydro-1,3- CH₂ O CH₂ Kalyuskiiet al., J. Org. Chem, 25, oxazin-4-one (10), 1989-1991 (1989); Linde etal., Arzneim. Forsch. 28, 937-939 (1978). tetrahydro-1,3- CH₂ O C═O Backet al., Tet. Lett., oxazin-2,4- 2651-4 (1977). dione morpholin-3- O CH₂CH₂ U.S. 3,092,630; Australian Patent one 9,063,019; Tulyaganov et al.,J.O.C.U.S.S.R., (Eng Tran) 6, 1311-1314 (1970); J.A.C.S., 58, 2338(1936). morpholin-3,5- O CH₂ C═O Hadley, et al., Tet. Lett, 24(1), 91dione (1983); 2,3-dihydro- O CH* CH* Vliet et al., Tetrahedron, 41(10),1,4-oxazin-3- 2007-2014 (1985). one tetrahydro-1,3- CH₂ S CH₂ Krus etal., Zh.Org.Khim., thiazin-4-one 24(8), 1576, (1988); Bergmann et al.,Recl. Trav. Chim. Pays-Bas., 78, 327-330 (1959); Nagakura et al.,Heterocycles, 3, 453 (1975). tetrahydro-1,3- CH₂ S C═O Hendry et al.,JACS, 80, thiazin-2,4- 973 (1958); Sohda et al., Chem. dione Pharm.Bull., 30, 3563 (1982); U.S. 4,352,929. tetrahydro-1,2- CH₂ CH₂ SKharasch, J.O.C., 28, 1901-1902 thiazin-3-one (1963). thiomorpholin- SCH₂ CH₂ Davies, J. Chem. Soc., 3-one 117, 298-306 (1920). thiomorpholin-S CH₂ C═O Schulze, Zeitschrift Fur Chem., 3,5-dione 182 (1866); Wolfe etal., J.O.C., 35, 3600-7 (1970). 2,3-dihydro- S CH* CH* Hojo et al.,Synthesis, 272 (1979); 1,4-thiazin-3- Masuda et al., Tet. Lett., one32(6) 1195 (1991). hexahydro- CH₂ CH₂ NH Hwang et al., Heterocycles,1,2-diazin-3- 36(2), 219 (1993); Taylor et al., one J.O.C., 52, 4107(1987). 4,5-dihydro- CH₂ CH* N* Reichett et al., Synthesis,2H-pyridazin- 9, 786-787 (1984); 3-one Amorosa, Ann. Chim. (Rome), 49,322-329 (1959). hexahydro-1,3- CH₂ NH CH₂ Yamamoto et al., Synthesis,diazin-4-one 6, 686, 1985; Skaric et al., Croat. Chem. Acta., 38, 1-4(1966). hexahydro-1,3- CH₂ NH C═O Yamamoto et al., Synthesis, 6,diazin-2,4- 686, 1985; Zee-Cheng et al., dione J. Org. Chem., 26, 1877(1961); Beckwith et al., J. Chem. Soc., C, 2756 (1968). piperazin-2- NHCH₂ CH₂ E.P. 264,261; J.A.C.S., 51, 3074 one (1929); Rees, J. Het.Chem., 24, 1297 (1987); US 3,037,023. piperazin-2,6- NH CH₂ C═OJ.A.C.S., 51, 3074 (1929); US dione 3,037,023. tetrahydro- S CH₂ NHJapanese Pat. 3,083,972 (1991); 1,3,4- Matsubara et al., Chem.Pharm.thiadiazin-5- Bull., 32(4), 1590 (1984). one 5,6-dihydro- S CH* N*Matsubara et al., Chem.Pharm. 1,3,4- Bull., 32(4) 1590 (1984).thiadiazin-5- one 1,3,4- O CH₂ NH Bennouna, et al., J. Hetero.oxadiazin-5- Chem, 16, 161 (1979). one 5,6-dihydro- O N* CH* JapanesePat. 3,148,267. 1,2,4- oxadiazin-5- one tetrahydro- O NH CH₂ JapanesePat. 3,148,267. 1,2,4- oxadiazin-5- one 1,2,4-triazin-5- NH NH CH₂Anderson et al., Tet., 39, one 3419 (1983); Schulz et al., Chem. Ber.,122, 1983 (1989). tetrahydro- O NH CH₂ Hussein, Hetercycles, 26, 1,2,4-163 (1987). oxadiazin-5- one 5,6-dihydro- O N* CH* Hussein, Hetercycles,26, 1,2,4- 163 (1987). oxadiazin-5- one 1,2,4- O NH C═O Rajagopalan etal., J.C.S. Chem. oxadiazin-3,5- Commun., 167 (1970). dione1,2,4-triazin-6- NH CH₂ NH Anderson et al., Tetrahedron, one 39(20),3419 (1983); Schulz et al., Chem. Ber., 122, 1983 (1989).

[0196] TABLE 3 7 MEMBERED HETEROCYCLES IV (Y = —L—M—P—Q—)

Name L M P Q Reference hexahydro- CH₂ CH₂ CH₂ O Amiaiky et al.,Synthesis, 5, 1,2- 426-428, (1982). oxazepin-3- one hexahydro- CH₂ CH₂ OCH₂ Bergmann et al., Recl. Trav. 1,3- Chim. Pays-Bas., 78, 327-330oxazepin-4- (1959). one hexahydro- O CH₂ CH₂ CH₂ Brown et al., J. Chem.Soc., 1,4- Perkin Trans., 1, 557 (1987); oxazepin-3- Farberow et al.,Zh. Obshch. one Khim., 25, 133-135 (1955); Grouiller et al., J.Heterocycl. Chem., 13, 853-859 (1976). hexahydro- O CH₂ CH₂ C═O See“Detailed Description”. 1,4- oxazepin- 3,5-dione 2,3,5,6- C═O O CH₂ CH₂Brown et al., Synth. tetrahydro- Commun., 18, 1801 (1988). 1,4-oxazepin- 5,7-dione hexahydro- CH₂ O CH₂ CH₂ Farberow et al., Zh.Obshch. 1,4- Khim., 25, 133-135 (1955); oxazepin-5- Kato et al., Chem.Ph. Bull., one 17(12), 2405-2410 (1969). hexahydro- CH₂ CH₂ O C═O See“Detailed Description”. 1,3- oxazepin 2,4-dione hexahydro- CH₂ CH₂ CH₂ SBlack, J. Chem. Soc. C, 1708- 1,2- 1710 (1966); Can. J. Chem.,thiazepin-3- 49, 2612-2616 (1971); one J. Org. Chem, 46, 7, 1239-1243(1981); and J. Org. Chem., 25, 1953- 1956 (1960); DE 1,195,317.hexahydro- S CH₂ CH₂ CH₂ Hill et al., JACS, 95(9), 1,4- 2923-2927(1973). thiazepin-3- one 2,3,4,5- S CH* CH* CH₂ Defoin et al.,Helv.Chim. tetrahydro- Acta., 68, 1998 (1985). 1,4- thiazepin-3- onehexahydro- S CH₂ CH₂ C═O See “Detailed Description”. 1,4- thiazepin3,5-dione hexahydro- CH₂ S CH₂ C═O See “Detailed Description”. 1,4-thiazepin- 3,5-dione 2,3,6,7- CH₂ S CH₂ CH₂ Jakob et al., Ber. Deutschtetrahydro- Chem. Ges., 96, 88 (1963). 1,4- thiazepin-5- one6,7-dihydro- CH₂ S CH* CH* Yamamoto et al., Ang. Chem. 1,4- Int. Ed.Engl., 25(7), thiazepin-5- 635 (1986). one hexahydro- CH₂ CH₂ S C═OHanefield et al., Liebigs Ann. 1,3- Chem., 4, 337-344 (1992). thiazepin-2,4-dione hexahydro- CH₂ CH₂ CH₂ N Rutjes et al., Tetrahedron 1,2-Lett., 32, 45, 6629-6632 diazepin-3- (1991); and Fritschi et al., oneHelv. Chem. Acta., 74, 8, 2024-2034 (1991). hexahydro- CH₂ CH₂ NH C═OBreckenridge, J.Chem. Res., 1,3- Miniprint, 6, 166 (1982); diazepin-Gunawardane, Indian J. 2,4-dione Chem. Sect. A., 27, 5, 380-386 (1988).hexahydro- NH CH₂ CH₂ CH₂ U.S. 4,814,443; Poppelsdorf 1,4- et al., J.Org. Chem., 26, diazepin-2- 131-134 (1961); Ziegler one et al., J. Med.Chem., 33, 1, 142-146 (1990). hexahydro- CH₂ NH CH₂ CH₂ Crombie et al.,J.Chem.Soc. 1,4- Chem.Commun., 959 (1983); diazepin-5- Groves et al,J.A.C.S., 106(3), one 630 (1984). hexahydro- C═O N CH₂ CH₂ Kappe et al.,Angew. 1,4- Chem. Int. Ed. Engl., 13, diazepin- 491 (1974); Bonsignoreet al., 5,7-dione Heterocycles, 26(6), 1619 (1987). hexahydro- S C═O NHCH₂ Vass, Synthesis, 10, 1,3,5- 817 (1986). thiadiazepin- 2,6-dione4,5,6,7- S CH* N* CH₂ Vass et al., Synthesis, 10, 817 tetrahydro-(1986). 1,3,5- thiadiazepin- 6-one 2,3,5,6- CH* N* NH C═O Hasnaoui etal., Rec. tetrahydra- Trav. Chim. P.-Bas, 1,2,4- 99, 301 (1980).triazepin-3, 5-dione

[0197] Compounds of the formula IV, wherein Y is —L—M—P—Q, and L issulfur or oxygen, M and P are —CH₂— and Q is —(C═O)—, can be preparedaccording to the following procedure. Said compound of the formula IV,depicted below,

 IV (Y═L—M—P—Q, L is sulfur or oxygen, M═P═—CH₂—, Q═—(C═O)—)

[0198] wherein L is sulfur or oxygen, is prepared by reacting ananhydride of the formula

[0199] wherein L is sulfur or oxygen , with an amine of the formulaR³NH₂, according to the method detailed by Meyers (JOC 54 (17) 4243(1989)), Fickenscher (Arch. Pharm., 307, 520 (1976)) or Cole et al., (J.Med. Chem., 13, 565 (1970)).

[0200] The anhydride of the formula XXXI can be prepared by reacting adiacid of the formula

[0201] wherein L is sulfur or oxygen, with acetic anhydride, accordingto the methods described in Vogel's Textbook of Practical OrganicChemistry, 499-501 (4th Ed., Longman House, London UK, 1970).

[0202] The compound of the formula XXX is commercially available or canbe made according to the procedure of Woodward and Eastman, J.A.C.S.,68, 2229 (1946).

[0203] Compounds of the formula IV, wherein Y is —L—M—P—Q, and L and Mare carbon, P is oxygen and Q is —(C═O)—, can be prepared according tothe following procedure. Said compound of the formula IV, depictedbelow,

 IV (Y═L—M—P—Q, L═M═CH₂, P═oxygen, Q═—(C═O)—)

[0204] is prepared from a compound of the formula

[0205] according to the method described by Back et al., Tet. lett.,2651-2654 (1977). The compound of the formula XXXIV can be preparedaccording to the method of Ksander, et al., JOC, 42, (7), 1180-1185(1977).

[0206] Compounds of the formula IV, wherein R³ is hydrogen (compounds ofthe formula IVA), may be alkylated to form the corresponding compoundswherein R³ is not hydrogen using standard techniques available to thoseskilled in the art, e.g., by (a) generation of the anion of the desiredcompound of formula IVA using a strong base/polar solvent system such asNaH/THF, NaH/DMF or n-butyllithium/THF (n-buLi/THF), at a temperaturefrom about −30° C. to about the reflux temperature of the solvent, for aperiod of about 5 minutes to about 24 hours, and (b) treatment of theanion with an alkylating agent of the formula R³L′ wherein L′ is aleaving group such as chloro, bromo, iodo or mesylate. This process isdepicted below.

[0207] The foregoing conversion of compounds of the formula IVA to thoseof the formula IVB may also be achieved using phase transfer catalysisconditions as described by Takahata et al, Heterocycles, 1979, 12(11),pp. 1449-1451.

[0208] Compounds of the formula IVB wherein R³ is aryl or heteroaryl canbe prepared from compounds of the formula IVA by reaction with an arylor heteroaryl reagent of the formula R³L′, wherein L′ is a leaving groupsuch as chloro, bromo or iodo, in the presence of a catalyst such ascopper (O) or copper (I) (such as copper, copper-bronze, or copperbromide) and a base, such as sodium hydride, potassium carbonate, orsodium carbonate. The reaction may be run neat or with a polar solventsuch as dimethyl formamide, or dimethyl sulfoxide. This reaction,referred to as an Ullmann condensation, is described by Yamamoto &Kurata, Chem. and Industry, 737-738 (1981).

[0209] The compounds of formula R¹H used in the preparation ofintermediates of the formula II are readily available or may be preparedusing standard methods of organic synthesis known to those skilled inthe art and adapted from procedures disclosed in the chemicalliterature. For example, the preparation of compounds of the formulaR¹H, wherein R¹ is G¹, may be accomplished using the following reactionsequence, beginning with commercially available N-tert-butoxycarbonylpiperazine (VI):

[0210] Alkylation of the compound of formula VI with a compound of theformula R⁶L′ wherein L′ is a leaving group, and is defined as Q isdefined above and R⁶ is (C₁-C₆)alkyl, aryl-(C₁-C₄)alkyl wherein the arylmoiety is phenyl or naphthyl, or heteroaryl-(CH₂)_(q)—, wherein q iszero, one, two, three or four, and the heteroaryl moiety is selectedfrom pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,and benzisothiazolyl, in the presence of an acid scavenger (e.g., sodiumbicarbonate (NaHCO₃), potassium bicarbonate (KHCO₃), sodium carbonate(Na₂CO₃) or potassium carbonate (K₂CO₃)), in a polar solvent such asacetone at a temperature of about 10° C. to about the reflux temperatureof the solvent, will yield the intermediate of formula VII. Removal ofthe tert-butoxycarbonyl group can be accomplished using acidicconditions, e.g., HBr in acetic acid or trifluoroacetic acid until thereaction is judged to be complete.

[0211] Compounds of the formula II, wherein R¹ is tetrahydropyridine orpiperidine (i.e. compounds of the formula G²) and R² is hydrogen, can beprepared from the 2-bromobenzaldehyde of formula III, many of which arecommercially available, as depicted in Scheme 2. Referring to Scheme 2,the compound of formula III is first converted into a protected aldehydeof the formula XIV, wherein P represents the entire protected aldehydeor ketone moiety, using methods well known in the art. For example, the1,3-dioxolane derivative of the aldehyde may be prepared according tothe method described by J. E. Cole et al., J. Chem. Soc., 244 (1962), byrefluxing a solution of the aldehyde of formula III and 1,3-propanediolin anhydrous benzene with a catalytic amount of p-toluenesulfonic acid.When R² of formula III is not hydrogen, the ketone can be protectedusing an appropriate protecting group. Appropriate protecting groups canbe chosen from many such groups based on the presence and nature of thesubstituent X. Examples of suitable protecting groups may be found in T.W. Greene and P. Wuts, Protecting Groups in Organic Synthesis, JohnWiley & Sons, 2nd Edition, New York, 1991. The most preferred protectinggroups are those that are resistant to catalytic hydrogenation (e.g.,1,3-dioxolane), which would therefore allow for the subsequentreduction, if required, of the carbon-carbon double bond of thetetrahydropyridines of formula XVIA.

[0212] Compounds of the formula XIV can then be treated withvinylstannanes of the formula

[0213] for example, 1-BOC-4-trimethylstannyl-1,2,5,6-tetrahydropyridine(wherein BOC refers to tert-butyloxycarbonyl), in the presence of acatalyst, to form the corresponding compound of formula XVIA. Palladiumis the preferred catalyst (for example, ((C₆H₅)₃P)₄Pd or Pd₂(dba)₃),wherein dba refers to dibenzylidene acetone. Suitable solvents for theaforesaid reaction include neat, acetonitrile, dimethylformamide,N-methyl-2-pyrrolidinone, preferably dimethylformamide. This reaction isconveniently run at about 20° C. to about 160° C., preferably about 60°C. to about 130° C. This reaction may be carried out as described in“Palladium-catalyzed Vinylation of Organic Halides” in OrganicReactions, 27, 345-390, (W. G. Dauben, Ed., John Wiley & Sons, Inc., NewYork, N.Y., 1982).

[0214] Compounds of the formula XVIA can be converted into compounds ofthe formula II, wherein R¹ is tetrahydropyridine by removal of thealdehyde or ketone protecting group. The protecting group for thealdehyde or ketone, P, can be converted into the unprotected ketone oraldehyde of the formula —C(═O)R² using one or more of the techniquesdescribed in Greene, for example, stirring a solution of the compound offormula XVI in THF and 5% hydrochloric acid at room temperature for 20hours.

[0215] Alternatively, compounds of formula XVIA can be converted intocompounds of the formula II, where R¹ is piperidine (G²), by catalytichydrogenation of the tetrahydropyridine of formula XVIA, from theprevious paragraph, using standard methods known in the art, generallyusing palladium on carbon as the catalyst, to form the correspondingcompounds of formula XVIB. This reaction is typically performed in aninert solvent, such as ethanol or ethyl acetate, either with or withouta protic acid such as acetic acid or hydrochloric acid (HCl). Aceticacid is preferred. The protecting groups on G² (e.g., BOC) can beremoved using one or more of the techniques described in Greene,referred to above, for example, stirring the compound of formula XVI inethyl acetate and 3 molar hydrochloric acid at about room temperaturefor about 30 minutes. The protecting group for the aldehyde or ketone,P, can be converted into the unprotected ketone or aldehyde as describedabove.

[0216] Compounds of the formula XIV from reaction Scheme 2 may also betreated with alkyllithium reagents, for example n-butyllithium,sec-butyllithium or tert-butyllithium, preferably n-butyllithium in aninert solvent, as shown in Scheme 3, to form the intermediate lithiumanion of formula XVII. Suitable solvents for this reaction include, forexample, ether or tetrahydrofuran, preferably tetrahydrofuran. Reactiontemperatures can range from about −110° C. to about 0° C. Theintermediate lithium anions of formula XVII can then be further reactedwith a suitable electrophile, selection of which depends on the presenceand nature of the substituent. Suitable electrophiles for use inpreparing compounds of the formula II wherein R¹ is a group of theformula G² include, for example, carbonyl derivatives or alkylatingagents (e.g., 1-BOC4-piperidone). In the case where an aldehyde orketone is used as the electrophile, the hydroxy group must be removedfrom the intermediate of formula XVIII, as depicted below, in order toform the corresponding compound of formula II.

[0217] This step may be accomplished by one of several standard methodsknown in the art. For example, a thiocarbonyl derivative such as axanthate may be prepared and removed by free radical processes, both ofwhich are known to those skilled in the art. Alternatively, the hydroxylgroup may be removed by reduction with a hydride source such astriethysilane under acidic conditions, using, for example,trifluoroacetic acid or boron trifluoride. The reduction reaction can beperformed neat or in a solvent such as methylene chloride. A furtheralternative would be to first convert the hydroxyl group to a suitableleaving group, such as tosylate or chloride, using standard methodsknown in the art, and then to remove the leaving group with anucleophilic hydride, such as, for example, lithium aluminum hydride.The latter reaction is typically performed in an inert solvent such asether or tetrahydrofuran. Also, a reducing agent may be used toreductively remove the benzylic substituent. Suitable reducing agentsinclude, for example, Raney nickel in ethanol and sodium or lithium inliquid ammonia. Another alternative method for removing the hydroxylgroup is to first dehydrate the alcohol of formula XVIII to an olefin ofthe formula XVIA (i.e. see Scheme 2) with a reagent such as Burgess salt(J. Org. Chem., 38, 26 (1973)) and then to catalytically hydrogenate thedouble bond under standard conditions with a catalyst such as palladiumon carbon. The alcohol may also be dehydrated to the olefin by treatmentwith acids such as p-toluenesulfonic acid.

[0218] Compounds of the formula II, wherein R¹ is G² and R⁶ is hydrogen,can be converted into the corresponding compounds of the formula II,wherein R¹ is G² and R⁶ is other than hydrogen, by reacting them with acompound of the formula R⁶L′, as described above in Scheme 1, forpreparing compounds of the formula VII.

[0219] Unless indicated otherwise, the pressure of each of the abovereactions is not critical. Generally, the reactions will be conducted ata pressure of about one to about three atmospheres, preferably atambient pressure (about one atmosphere).

[0220] The compounds of the formula I which are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate a compound of the formula Ifrom the reaction mixture as a pharmaceutically unacceptable salt andthen simply convert the latter back to the free base compound bytreatment with an alkaline reagent, and subsequently convert the freebase to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the base compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isobtained.

[0221] The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the base compounds of this inventionare those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0222] Those compounds of the formula I which are also acidic in nature,e.g., where R³ includes a COOH or tetrazole moiety, are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline-earth metalsalts and particularly, the sodium and potassium salts. These salts areall prepared by conventional techniques. The chemical bases which areused as reagents to prepare the pharmaceutically acceptable base saltsof this invention are those which form non-toxic base salts with theherein described acidic compounds of formula I. These non-toxic basesalts include those derived from such pharmacologically acceptablecations as sodium, potassium, calcium and magnesium, etc. These saltscan easily be prepared by treating the corresponding acidic compoundswith an aqueous solution containing the desired pharmacologicallyacceptable cations, and then evaporating the resulting solution todryness, preferably under reduced pressure. Alternatively, they may alsobe prepared by mixing lower alkanolic solutions of the acidic compoundsand the desired alkali metal alkoxide together, and then evaporating theresulting solution to dryness in the same manner as before. In eithercase, stoichiometric quantities of reagents are preferably employed inorder to ensure completeness of reaction and maximum product yields.

[0223] Compounds of the formula I and their pharmaceutically acceptablesalts (hereinafter also referred to, collectively, as “the activecompounds”) are useful psychotherapeutics and are potent agonists and/orantagonists of the serotonin 1A (5-HT_(1A)) and/or serotonin 1D(5-HT_(1D)) receptors. The active compounds are useful in the treatmentof hypertension, depression, generalized anxiety disorder, phobias(e.g., agoraphobia, social phobia and simple phobias), posttraumaticstress syndrome, avoidant personality disorder, sexual dysfunction(e.g., premature ejaculation), eating disorders (e.g., anorexia nervosaand bulimia nervosa), obesity, chemical dependencies (e.g., addictionsto alcohol, cocaine, heroin, phenolbarbitol, nicotine andbenzodiazepines), cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders (e.,dementia, amnestic disorders, and age-related cognitive decline (ARCD)),Parkinson's diseases (e.g., dementia in Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias), endocrinedisorders (e.g., hyperprolactinaemia), vasospasm (particularly in thecerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders (involving changes in motility and secretion), negativesymptoms of schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome,stress incontinence, Tourette syndrome, trichotillomania, kleptomania,male impotence, cancer (e.g., small cell lung carcinoma), chronicparoxysmal hemicrania and headache (associated with vascular disorders).

[0224] The affinities of the compounds of this invention for the variousserotonin-1 receptors can be determined using standard radioligandbinding assays as described in the literature. The 5-HT_(1A) affinitycan be measured using the procedure of Hoyer et al. (Brain Res., 376, 85(1986)). The 5-HT_(1D) affinity can be measured using the procedure ofHeuring and Peroutka (J. Neurosci., 7, 894 (1987)).

[0225] The in vitro activity of the compounds of the present inventionat the 5-HT_(1D) binding site may be determined according to thefollowing procedure. Bovine caudate tissue is homogenized and suspendedin 20 volumes of a buffer containing 50 mM TRIS.hydrochloride(tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7. Thehomogenate is then centrifuged at 45,000G for 10 minutes. Thesupernatant is then discarded and the resulting pellet resuspended inapproximately 20 volumes of 50 mM TRIS.hydrochloride buffer at pH 7.7.This suspension is then pre-incubated for 15 minutes at 37° C., afterwhich the suspension is centrifuged again at 45,000G for 10 minutes andthe supernatant discarded. The resulting pellet (approximately 1 gram)is resuspended in 150 ml of a buffer of 15 mM TRIS.hydrochloridecontaining 0.01 percent ascorbic acid with a final pH of 7.7 and alsocontaining 10 μM pargyline and 4 mM calcium chloride (CaCl₂). Thesuspension is kept on ice at least 30 minutes prior to use.

[0226] The inhibitor, control or vehicle is then incubated according tothe following procedure. To 50 μl of a 20 percent dimethylsulfoxide(DMSO)/80 percent distilled water solution is added 200 μl of tritiated5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloridecontaining 0.01 percent ascorbic acid at pH 7.7 and also containing 10μM pargyline and 4 μM calcium chloride, plus 100 nM of 8-hydroxy-DPAT(dipropylaminotetraline) and 100 nM of mesulergine. To this mixture isadded 750 μl of bovine caudate tissue, and the resulting suspension isvortexed to ensure a homogenous suspension. The suspension is thenincubated in a shaking water bath for 30 minutes at 25° C. Afterincubation is complete, the suspension is filtered using glass fiberfilters (e.g., Whatman GF/B-filters™). The pellet is then washed threetimes with 4 ml of a buffer of 50 mM TRIS.hydrochloride at pH 7.7. Thepellet is then placed in a scintillation vial with 5 ml of scintillationfluid (aquasol 2™) and allowed to sit overnight. The percent inhibitioncan be calculated for each dose of the compound. An IC₅₀ value can thenbe calculated from the percent inhibition values.

[0227] The activity of the compounds of the present invention for⁵-HT_(1A) binding ability can be determined according to the followingprocedure. Rat brain cortex tissue is homogenized and divided intosamples of 1 gram lots and diluted with 10 volumes of 0.32 M sucrosesolution. The suspension is then centrifuged at 900G for 10 minutes andthe supemate separated and recentrifuged at 70,000G for 15 minutes. Thesupernate is discarded and the pellet re-suspended in 10 volumes of 15mM TRIS.hydrochloride at pH 7.5. The suspension is allowed to incubatefor 15 minutes at 37° C. After pre-incubation is complete, thesuspension is centrifuged at 70,000G for 15 minutes and the supernatediscarded. The resulting tissue pellet is resuspended in a buffer of 50mM TRIS.hydrochloride at pH 7.7 containing 4 mM of calcium chloride and0.01 percent ascorbic acid. The tissue is stored at −70° C. until readyfor an experiment. The tissue can be thawed immediately prior to use,diluted with 10 μm pargyline and kept on ice.

[0228] The tissue is then incubated according to the followingprocedure. Fifty microliters of control, inhibitor, or vehicle (1percent DMSO final concentration) is prepared at various dosages. Tothis solution is added 200 μl of tritiated DPAT at a concentration of1.5 nM in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mMcalcium chloride, 0.01 percent ascorbic acid and pargyline. To thissolution is then added 750 μl of tissue and the resulting suspension isvortexed to ensure homogeneity. The suspension is then incubated in ashaking water bath for 30 minutes at 37° C. The solution is thenfiltered, washed twice with 4 ml of 10 mM TRIS.hydrochloride at pH 7.5containing 154 mM of sodium chloride. The percent inhibition iscalculated for each dose of the compound, control or vehicle. IC₅₀values are calculated from the percent inhibition values.

[0229] The compounds of formula I of the present invention described inthe following Examples were assayed for 5-HT_(1A) and 5-HT_(1D) affinityusing the aforementioned procedures. All such compounds of the inventionthat were tested exhibited IC₅₀'s less than 0.60 μM for 5-HT_(1D)affinity and IC₅₀'s less than 1.0 μM for 5-HT_(1A) affinity.

[0230] The agonist and antagonist activities of the compounds of theinvention at 5-HT_(1A) and 5-HT_(1D) receptors can be determined using asingle saturating concentration according to the following procedure.Male Hartley guinea pigs are decapitated and 5-HT_(1A) receptors aredissected out of the hippocampus, while 5-HT_(1D) receptors are obtainedby slicing at 350 mM on a McIlwain tissue chopper and dissecting out thesubstantia nigra from the appropriate slices. The individual tissues arehomogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using ahand-held glass-Teflon® homogenizer and centrifuged at 35,000×g for 10minutes at 4° C. The pellets are resuspended in 100 mM HEPES buffercontaining 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg(hippocampus) or 5 mg (substantia nigra) of protein per tube. Thefollowing agents are added so that the reaction mix in each tubecontained 2.0 mM MgCl₂, 0.5 mM ATP, 1.0 mM CAMP, 0.5 mM IBMX, 10 mMphosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 μM GTP and 0.5-1microcuries of [³²P]-ATP (30 Ci/mmol: NEG-003- New England Nuclear).Incubation is initiated by the addition of tissue to siliconizedmicrofuge tubes (in triplicate) at 30° C. for 15 minutes. Each tubereceives 20 μL tissue, 10 μL drug or buffer (at 10×final concentration),10 μL 32 nM agonist or buffer (at 10×final concentration), 20 μLforskolin (3 μM final concentration) and 40 μL of the preceding reactionmix. Incubation is terminated by the addition of 100 μL 2% SDS, 1.3 mMCAMP, 45 mM ATP solution containing 40,000 dpm [³H]-cAMP (30 Ci/mmol:NET-275- New England Nuclear) to monitor the recovery of CAMP from thecolumns. The separation of [³²P]-ATP and [³²P]-cAMP is accomplishedusing the method of Salomon et al., Analytical Biochemistry, 1974, 58,541-548. Radioactivity is quantified by liquid scintillation counting.Maximal inhibition is defined by 10 μM (R)-8-OH-DPAT for 5-HT_(1A)receptors, and 320 nM 5-HT for 5-HT_(1D) receptors. Percent inhibitionsby the test compounds are then calculated in relation to the inhibitoryeffect of (R)-8-OH-DPAT for 5-HT_(1A) receptors or 5-HT for 5-HT_(1D)receptors. The reversal of agonist induced inhibition offorskolin-stimulated adenylate cyclase activity is calculated inrelation to the 32 nM agonist effect.

[0231] The compounds of the invention can be tested for in vivo activityfor antagonism of 5-HT_(1D) agonist-induced hypothermia in guinea pigsaccording to the following procedure.

[0232] Male Hartley guinea pigs from Charles River, weighing 250-275grams on arrival and 300-600 grams at testing, serve as subjects in theexperiment. The guinea pigs are housed under standard laboratoryconditions on a 7 a.m. to 7 p.m. lighting schedule for at least sevendays prior to experimentation. Food and water are available ad libitumuntil the time of testing.

[0233] The compounds of the invention can be administered as solutionsin a volume of 1 ml/kg. The vehicle used is varied depending on compoundsolubility. Test compounds are typically administered either sixtyminutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a5-HT_(1D) agonist, such as[3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3-yl)-amine,which can be prepared as described in PCT publication WO93/111 06,published Jun. 10, 1993 which is administered at a dose of 5.6 mg/kg,s.c. Before a first temperature reading is taken, each guinea pig isplaced in a clear plastic shoe box containing wood chips and a metalgrid floor and allowed to acclimate to the surroundings for 30 minutes.Animals are then returned to the same shoe box after each temperaturereading. Prior to each temperature measurement each animal is firmlyheld with one hand for a 30-second period. A digital thermometer with asmall animal probe is used for temperature measurements. The probe ismade of semi-flexible nylon with an epoxy tip. The temperature probe isinserted 6 cm. into the rectum and held there for 30 seconds or until astable recording is obtained. Temperatures are then recorded.

[0234] In p.o. screening experiments, a “pre-drug” baseline temperaturereading is made at −90 minutes, the test compound is given at −60minutes and an additional −30 minute reading is taken. The 5-HT_(1D)agonist is then administered at 0 minutes and temperatures are taken 30,60, 120 and 240 minutes later.

[0235] In subcutaneous screening experiments, a pre drug baselinetemperature reading is made at −30 minutes. The test compound and5-HT_(1D) agonists are given concurrently and temperatures are taken at30, 60, 120 and 240 minutes later.

[0236] Data are analyzed with two-way analysis of variants with repeatedmeasures in Newman-Keuls post hoc analysis.

[0237] The active compounds of the invention can be evaluated asanti-migraine agents by testing the extent to which they mimicsumatriptan in contracting the dog isolated saphenous vein strip [P.P.A.Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)]. This effect can beblocked by methiothepin, a known serotonin antagonist. Sumatriptan isknown to be useful in the treatment of migraine and produces a selectiveincrease in carotid vascular resistance in the anesthetized dog. Thepharmacological basis of sumatriptan efficacy has been discussed in W.Fenwick et al., Br. J. Pharmacol., 96, 83 (1989).

[0238] The serotonin 5-HT₁ agonist activity can be determined by the invitro receptor binding assays, as described for the 5-HT_(1A) receptorusing rat cortex as the receptor source and [³H]-8-OH-DPAT as theradioligand [D. Hoyer et al. Eur. J. Pharm., 118, 13 (1985)]and asdescribed for the 5-HT_(1D) receptor using bovine caudate as thereceptor source and [³H]serotonin as the radioligand [R. E. Heuring andS. J. Peroutka, J. Neuroscience, 7, 894 (1987)]. Of the active compoundstested, all exhibited an IC₅₀ in either assay of 1 μM or less.

[0239] The compounds of formula I may advantageously be used inconjunction with one or more other therapeutic agents, for instance,different antidepressant agents such as tricyclic antidepressants (e.g.,amitriptyline, dothiepin, doxepin, trimipramine, butripyline,clomipramine, desipramine, imipramine, iprindole, lofepramine,nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g.,isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT re-uptakeinhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine),and/or with antiparkinsonian agents such as dopaminergicantiparkinsonian agents (e.g., levodopa, preferably in combination witha peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, orwith a dopamine agonist e.g., bromocriptine, lysuride or pergolide). Itis to be understood that the present invention covers the use of acompound of general formula (I) or a physiologically acceptable salt orsolvate thereof in combination with one or more other therapeuticagents.

[0240] Compounds of the formula I and the pharmaceutically acceptablesalts thereof, in combination with a 5-HT re-uptake inhibitor (e.g.,fluvoxamine, sertraline, fluoxetine or paroxetine), preferablysertraline, or a pharmaceutically acceptable salt or polymorph thereof(the combination of a compound of formula I with a 5-HT re-uptakeinhibitor is referred herein to as “the active combination”), are usefulpsychotherapeutics and may be used in the treatment or prevention ofdisorders the treatment or prevention of which is facilitated byenhanced serotonergic neurotransmission (e.g., hypertension, depression,generalized anxiety disorder, phobias, posttraumatic stress syndrome,avoidant personality disorder, sexual dysfunction, eating disorders,obesity, chemical dependencies, cluster headache, migraine, pain,Alzheimer's disease, obsessive-compulsive disorder, panic disorder,memory disorders (e.g., dementia, amnestic disorders, and age-associatedmemory impairment), Parkinson's diseases (e.g., dementia in Parkinson'sdisease, neuroleptic-induced Parkinsonism and tardive dyskinesias),endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularlyin the cerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders (involving changes in motility and secretion) chronicparoxysmal hemicrania and headache (associated with vascular disorders).

[0241] Serotonin (5-HT) re-uptake inhibitors, preferably sertraline,exhibit positive activity against depression; chemical dependencies;anxiety disorders including panic disorder, generalized anxietydisorder, agoraphobia, simple phobias, social phobia, and post-traumaticstress disorder; obsessive-compulsive disorder; avoidant personalitydisorder and premature ejaculation in mammals, including humans, due inpart to their ability to block the synaptosomal uptake of serotonin.

[0242] U.S. Pat. No. 4,536,518 describes the synthesis, pharmaceuticalcomposition and use of sertraline for depression and is herebyincorporated by reference in its entirety.

[0243] Activity of the active combination as antidepressants and relatedpharmacological properties can be determined by methods (1)-(4) below,which are described in Koe, B. et al., Journal of Pharmacology andExperimental Therapeutics, 226 (3), 686-700 (1983). Specifically,activity can be determined by studying (1) their ability to affect theefforts of mice to escape from a swim-tank (Porsolt mouse “behaviordespair” test), (2) their ability to potentiate5-hydroxytryptophan-induced behavioral symptoms in mice in vivo, (3)their ability to antagonize the serotonin-depleting activity ofp-chloroamphetamine hydrochloride in rat brain in vivo, and (4) theirability to block the uptake of serotonin, norepinephrine and dopamine bysynaptosomal rat brain cells in vitro. The ability of the activecombination to counteract reserpine hypothermia in mice in vivo can bedetermined according to the methods described in U.S. Pat. No.4,029,731.

[0244] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation.

[0245] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g, magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g, methyl or propyl p-hydroxybenzoates or sorbic acid).

[0246] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0247] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion Formulations for injection may bepresented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0248] The active compounds of the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0249] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0250] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (e.g., depression) is0.1 to 200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

[0251] Aerosol formulations for treatment of the conditions referred toabove (e.g., migraine) in the average adult human are preferablyarranged so that each metered dose or “puff” of aerosol contains 20 μgto 1000 μg of the compound of the invention. The overall daily dose withan aerosol will be within the range 100 μg to 10 mg. Administration maybe several times daily, for example 2, 3, 4 or 8 times, giving forexample, 1, 2 or 3 doses each time.

[0252] In connection with the use of an active compound of thisinvention with a 5-HT re-uptake inhibitor, preferably sertraline, forthe treatment of subjects possessing any of the above conditions, it isto be noted that these compounds may be administered either alone or incombination with pharmaceutically acceptable carriers by either of theroutes previously indicated, and that such administration can be carriedout in both single and multiple dosages. More particularly, the activecombination can be administered in a wide variety of different dosageforms, i.e., they may be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, sprays, aqueoussuspension, injectable solutions, elixirs, syrups, and the like. Suchcarriers include solid diluents or fillers, sterile aqueous media andvarious non-toxic organic solvents, etc. Moreover, such oralpharmaceutical formulations can be suitably sweetened and/or flavored bymeans of various agents of the type commonly employed for such purposes.In general, the compounds of formula I are present in such dosage formsat concentration levels ranging from about 0.5% to about 90% by weightof the total composition, i.e., in amounts which are sufficient toprovide the desired unit dosage and a 5-HT re-uptake inhibitor,preferably sertraline, is present in such dosage forms at concentrationlevels ranging from about 0.5% to about 90% by weight of the totalcomposition, i.e., in amounts which are sufficient to provide thedesired unit dosage.

[0253] A proposed daily dose of an active compound of this invention inthe combination formulation (a formulation containing an active compoundof this invention and a 5-HT re-uptake inhibitor) for oral, parenteral,rectal or buccal administration to the average adult human for thetreatment of the conditions referred to above is from about 0.01 mg toabout 2000 mg, preferably from about 0.1 mg to about 200 mg of theactive ingredient of formula I per unit dose which could beadministered, for example, 1 to 4 times per day.

[0254] A proposed daily dose of a 5-HT re-uptake inhibitor, preferablysertraline, in the combination formulation for oral, parenteral orbuccal administration to the average adult human for the treatment ofthe conditions referred to above is from about 0.1 mg to about 2000 mg,preferably from about 1 mg to about 200 mg of the 5-HT re-uptakeinhibitor per unit dose which could be administered, for example, 1 to 4times per day.

[0255] A preferred dose ratio of sertraline to an active compound ofthis invention in the combination formulation for oral, parenteral orbuccal administration to the average adult human for the treatment ofthe conditions referred to above is from about 0.00005 to about 20,000,preferably from about 0.25 to about 2,000.

[0256] Aerosol combination formulations for treatment of the conditionsreferred to above in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains from about 0.01 μgto about 100 mg of the active compound of this invention, preferablyfrom about 1 μg to about 10 mg of such compound. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

[0257] Aerosol formulations for treatment of the conditions referred toabove in the average adult human are preferably arranged so that eachmetered dose or “puff” of aerosol contains from about 0.01 mg to about2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferablyfrom about 1 mg to about 200 mg of sertraline. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

[0258] As previously indicated, a 5-HT re-uptake inhibitor, preferablysertraline, in combination with compounds of formula I are readilyadapted to therapeutic use as antidepressant agents. In general, theseantidepressant compositions containing a 5-HT re-uptake inhibitor,preferably sertraline, and a compound of formula I are normallyadministered in dosages ranging from about 0.01 mg to about 100 mg perkg of body weight per day of a 5-HT re-uptake inhibitor, preferablysertraline, preferably from about 0.1 mg. to about 10 mg per kg of bodyweight per day of sertraline; with from about 0.001 mg. to about 100 mgper kg of body weight per day of a compound of formula I, preferablyfrom about 0.01 mg to about 10 mg per kg of body weight per day of acompound of formula I, although variations will necessarily occurdepending upon the conditions of the subject being treated and theparticular route of administration chosen.

[0259] The following Examples illustrate the preparation of thecompounds of the present invention. Melting points are uncorrected. NMRdata are reported in parts per million (δ) and are referenced to thedeuterium lock signal from the sample solvent (deuteriochloroform unlessotherwise specified). Specific rotations were measured at roomtemperature using the sodium D line (589 nm). Commercial reagents wereutilized without further purification. THF refers to tetrahydrofuran.DMF refers to N,N-dimethylformamide. Chromatography refers to columnchromatography performed using 32-63 μm silica gel and executed undernitrogen pressure (flash chromatography) conditions. Room or ambienttemperature refers to 20-25° C. All non-aqueous reactions were run undera nitrogen atmosphere for convenience and to maximize yields.Concentration at reduced pressure means that a rotary evaporator wasused.

Example 13-(4-Chlorobenzyl-5-[2-(4-methylpiperazin-1-yl-benzylidene]-imidazolidine-2,4-dione

[0260] Under a nitrogen atmosphere in a flame-dried flask, sodiumhydride (43 mg, 1.07 mmol, 60% oil dispersion) was washed with hexanesand then treated with tetrahydrofuran (THF) (8 mL), followed by3-(4-chlorobenzyl)-imidazolidine-2,4dione (235 mg, 1.04 mmol) and2-(4-methylpiperazin-1-yl)-benzaldehyde (209 mg, 1.02 mmol), and anadditional 2 mL of THF. After refluxing the mixture overnight, thesolvent was removed and the residue was treated with aqueous ammoniumchloride and aqueous sodium bicarbonate to a pH of 8, then extractedwith methylene chloride. The organic extracts were washed with aqueoussodium chloride, dried and concentrated in vacuo to a yellow foam. Thefoam was crystallized from hot ethyl acetate : hexanes to give a solid,240 mg (57%).

[0261] M.p. 185-187° C. Mass spectrum: 411 (M⁺¹). ¹H-NMR (CDCl₃) δ9.45(1H, s), 7.37-7.24 (4H, m), 7.16-7.09 (2H, m), 6.72 (1H, s), 4.72 (2H,s), 3.02 (4H, br s), 2.34 (3H, 2). Elemental analysis calculated forC₂₂H₂₃N₄O₂Cl.0.5 H₂O: C 62.93,H 5.76, N 13.34. Found: C 63.33, H 5.58, N13.58.

[0262] The following examples were prepared by an analogous procedure tothat of Example 1, except where indicated.

EXAMPLE 23-(4-Chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-imidazolidine-2,4-dione

[0263] M.p. 193-193.5° C. Mass spectrum 397 (M⁺¹). Elemental analysiscalculated for C₂₁H₂₁N₄O₂Cl.0.5 CH₃CN: C63.31, H 5.43, N 15.10. Found: C62.93, H 5.50, N 15.10.

EXAMPLE 33(4-Chlorobenzyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4dionehydrochloride hydrate

[0264] M.p. 240-242° C. Mass spectrum 428 (M⁺¹). Elemental analysiscalculated for C₂₂H₂₂N₃O₂SCl.HCl.0.25 H₂O: C 56.35,H 5.05, N 8.96.Found: C 56.18, H 5.03 , N 8.70.

EXAMPLE 44-Benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one

[0265] M.p. 106-108° C. Mass spectrum 394 (M⁺¹). Elemental analysiscalculated for C₂₃H₂₇N₃OS: C 70.20, H 6.91. N 10.68. Found: C 70.19, H6.99, N 10.72. ¹H-NMR (CDCl₃) δ8.10 (1H, s), 7.64 (1H, dd), 7.53-7.26(6H, m), 7.08-6.97 (2H, m), 4.80 (2H, s), 3.69 (2H, sym m), 3.01 (4H,t), 2.88 (2H, sym m), 2.63 (4H, br s), 2.38 (3H, s).

EXAMPLE 54-(3,4-Dichlorobenzyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-onehydrochloride dihydrate

[0266] M.p. 90-115° C. Mass spectrum 462 (M+¹). Elemental analysiscalculated for C₂₃H₂₅N₃OSCl₂HCl.2 H₂O: C 51.64, H 5.65, N 7.86. Found: C51.83, H 5.76, N 7.64.

EXAMPLE 65-[2-(4-Methylpiperazin-1-yl)-benzylidene]-thiazolidine-2.4-dionehemihydrate

[0267] Yellow solid, m.p. 105° C. (dec.). Mass spectrum 304 (M⁺¹).Elemental analysis calculated for C₁₅H₁₇N₃O₂S.0.5 H₂O: C 57.67,H 5.81, N13.45. Found: C 57.81, H 6.48 N 13.20. ¹H-NMR (CDCl₃, 400 MHz) δ8.05(1H, s), 7.68 (1H, d), 7.36 (1H, dt), 7.12-7.03 (2H, m), 3.12-3.02 (5H,m), 2.71 (4H, br s), 2.41 (3H, s).

EXAMPLE 73-(4-Chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dionehydrochloride hemihydrate

[0268] Under a nitrogen atmosphere in a flame-dried flask, a mixture of3-(4-chlorophenyl)-thiazolidine-2,4-dione (158 mg, 0.694 mmol),2-(4-methylpiperazin-1-yl)-benzaldehyde (142 mg, 0.694 mmol) and sodiumacetate (171 mg, 2.08 mmol) in 1 mL of glacial acetic acid was heated toreflux for approximately 6 hours and cooled to room temperature.Saturated aqueous sodium carbonate (Na₂CO₃) was added until the pH wasabout 10 and the mixture was extracted several times with methylenechloride. The organic layers were washed with brine, saturated sodiumchloride, dried and evaporated to a brown solid which was recrystallizedfrom ethyl acetate.

[0269] M.p. 187-189° C. Elemental analysis calculated for C₂₁H₂₀N₃O₂ClS:C 60.94, H 4.87, N 10.15. Found: C 60.57, H 4.95, N 10.00.

[0270] The above compound (56 mg) was treated with diethyl ethersaturated with hydrogen chloride gas and the product was recrystallizedfrom hot ethanol to yield3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dionehydrochloride hemihydrate as a solid, 54 mg, m.p. 254-258° C.

[0271] Elemental analysis calculated for C₂₁H₂₀N₃O₂ClS.HCl.0.5 H₂O: C54.90, H 4.83, N 9.15. Found: C 55.07, H 5.01, N 8.78. ¹H-NMR (DMSO-d₈)δ0.84 (1H, br s), 7.60 (2H, d), 7.52-7.45 (4H, m), 7.24 (2H, t).3.53-3.05 (8H, m), 2.80 (3H, s).

[0272] The following examples were prepared by an analogous procedure tothat of Example 7, except as indicated.

EXAMPLE 83-(4-[Trifluoromethyl]-phenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dionehydrochloride dihydrate

[0273] M.p. 159-177° C. Mass spectrum 448 (M⁺¹). Elemental analysiscalculated for C₂₂H₂₀N₃O₂SF₃.HCl.2 H₂O: C 50.82, H 4.85, N 8.08. Found:C 51.04, H 4.66, N 8.01.

EXAMPLE 92-[2-(4-Methylpiperazin-1-yl)-benzylidene]4-(4-trifluoromethylphenyl)-thiomorpholin-3-onehydrochloride trihydrate

[0274] M.p. 128-134° C. Mass spectrum 448 (M⁺¹). ¹H-NMR (DMSO-d₆, 400MHz) δ10.66 (1H, br s), 7.79 (1H, s), 7.76 (2H, d), 7.66 (1H, d), 7.61(2H, d), 7.34 (1H, t), 7.15-7.10 (2H, m), 4.14 (2H, m), 3.43 (2H, br s),3.22 (2H, m), 3.21-3.00 (6H, m), 2.78 (3H, s).

EXAMPLE 102-[2-(4-Methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one

[0275] Sodium hydride (930 mg, 23.3 mmol of 60% oil dispersion) waswashed with hexanes under a nitrogen atmosphere and suspended in 100 mLof anhydrous THF. Thiomorpholin-3-one (1.0 g, 8.55 mmol) was added,followed immediately by 2-(4-methylpiperazin-1-yl)-benzaldehyde (1.58g., 7.75 mmol). The reaction was then heated to reflux overnight, cooledto room temperature and concentrated in vacuo. The residue was dissolvedin methylene chloride and washed with aqueous ammonium chloride (NH₄Cl)and saturated brine and then dried with MgSO₄. Purification using flashchromatography gave2-{hydroxy-[2-(4-methylpiperazin-1-yl)phenyl]-methyl}-thiomorpholin-3-oneas a white solid, m.p. 137-139° C. Mass spectrum 322 (M⁺¹).

[0276] A mixture of 190 mg (0.6 mmol) of the preceding intermediate in25 mL of toluene was treated with 135 mg (0.71 mmol) ofp-toluenesulfonic acid and refluxed overnight with a Dean-Starkcondenser to collect the water which azeotroped. After cooling, thesolvent was removed and the residue was dissolved in methylene chloride,washed with saturated aqueous sodium carbonate (Na₂CO₃) and saturatedbrine, dried with magnesium sulfate and concentrated in vacuo to a brownfoam. The free base was crystallized from ethyl acetate/hexanes to yielda crystalline solid.

[0277] M.p. 133-135° C; mass spectrum 304 (M+¹). Elemental analysiscalculated for C₁₆H₂₁N₃OS: C 63.34, H 6.98, N 13.85. Found: C 63.17, H7.12, N 13.67

[0278] The following examples were prepared by an analogous procedure toExample 10, except where indicated.

EXAMPLE 114-(3,4-Dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one

[0279] M.p. 146-147° C. Mass spectrum 466 (M⁺¹), 468.

EXAMPLE 124(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-morpholin-3-one

[0280] M.p. 169-171° C. (decomp.). Mass spectrum 432 (M⁺), 434, 436.

EXAMPLE 132-[2,4-Dibromo-6-(4-methylpiperazin-1-yl)-benzylidene]4-(3,4-dichlorophenyl)-thiomorpholin-3-one.

[0281] M.p. 166-168° C. Mass spectrum 607 (M⁺¹). Elemental analysiscalculated for C₂₂H₂₁N₃OSBr₂. C 43.59, H 3.49, N 6.93. Found: C 43.56, H3.25, N 6.89.

EXAMPLE 144-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3one

[0282] M.p. 171-173° C. Mass spectrum 448 (M+¹).

[0283] Converting to the hydrochloride salt, using 1.0M HCl in ether,and recrystallizing from isopropanol gave pale yellow crystals.

[0284] M.p. 155-157° C. Elemental analysis calculated forC₂₂H₂₃N₃OSCl₂.HCl1.5 H₂O: C 51.62, H 5.32, N 8.21. Found: C 51.81, H5.02, N 8.45.

EXAMPLE 154-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzyl-thiomorpholin-3-onehydrochloride trihydrate

[0285] A slurry of4-(3,4-dichlorophenyl)-2-[2-(4-methyl-piperazin-1-yl)-benzylidene]-thiomorpholin-3-onein (201 mg, 0.5 mmol) 3 mL of anhydrous methanol (3 ml) was treated withsamarium iodide (SmI₂) (15 ml of 0.1 m) in THF (Aldrich Chemical Co.,Milwaukee, Wis.) and stirred overnight at room temperature under anitrogen atmosphere. An additional 5 mL of SmI₂ solution was added and,after an additional one hour, the solvent was removed in vacuo and theresidue was flash chromatographed using ethyl acetate/methanol to elutethe free base of the product. The hydrochloride salt was prepared, using1.0M HCl in ether, to produce a light tan solid.

[0286] M.p. 105-110° C. (foam). Elemental analysis calculated forC₂₂H₂₁N₃OSCl₂.HCl3 H₂O: C 48.85, H 5.96, N 7.77. Found: C 48.95, H 5.58,N 7.51. ¹H-NMR (CDCl₃, 400 MHz, free base) δ7.45-7.41 (2H, m), 7.17-7.13(2H, m), 7.06 (1H, t), 4.16 (1H, m), 4.00-3.86 (2H, m), 3.53 (1H, dd),3.10-2.95 (7H, M), 2.61 (4H, br s), 2.37 (3H, s).

EXAMPLE 164-Methyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-onehydrochloride hemihydrate.

[0287] Under a nitrogen atmosphere, sodium hydride (49 mg, 1.24 mmol,60% oil dispersion) was washed with hexanes and layered with 6 mL ofanhydrous THF. After cooling to 0° C.,2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one (250 mg,0.825 mmol) was added and the reaction was stirred for 30 min. To theresulting solution was added iodomethane (62 μL, 0.99 mmol), followed 15minutes later by an additional 10 μL of iodomethane. After 30 min., thesolvent was removed in vacuo and the residue was dissolved in methylenechloride and washed with aqueous ammonium chloride and aqueous brine.After drying, the solvent was removed in vacuo and the residue waspurified by flash chromatography. The free base was converted into thehydrochloride salt as described in Example 15 to produce the titleproduct as a pale yellow solid.

[0288] M.p. 236-238° C. Mass spectrum 318 (M⁺¹). ¹H-NMR (DMSO-d₆+D₂O ,400 MHz) δ7.70 (1H, s), 7.48 (1H, d), 7.30 (1H, t), 7.11-7.04 (2H, m),3.69 (2H, br s), 3.55-3.30 (2H, br s), 3.29-3.02 (4H, m), 2.97 (3H, s),2.90 (4H, br s), 2.79 (3H, s). Elemental analysis calculated forC₁₇H₂₃N₃OS.HCl.0.5 H₂O: C 56.26, H 6.94, N 11.58. Found: C 56.22, H7.11, N 11.37

EXAMPLE 174-(3,4-Dichlorophenyl)-2-(2-piperazin-1-ylbenzylidene)-thiomorpholin-3-one.

[0289] Under a nitrogen atmosphere, a mixture of4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one(338 mg, 0.756 mmol) in 9 mL of anhydrous 1,2-dichloroethane was treatedwith α-chloroethyl chloroformate (98 μL 0.907 mmol) and refluxedovernight. The solvent was then removed in vacuo and 10 mL of methanolwas added and refluxed for 30 minutes. Following removal of the solvent,the residue was extracted into methylene chloride and washed withsaturated aqueous sodium carbonate (Na₂CO₃) and saturated brine, driedwith magnesium sulfate and concentrated to a foam. Flash chromatographyusing triethyl amine/methanol/ethyl acetate (1:2:97) gave the purifiedfree base of the title compound.

[0290] M.p. 198-200° C. Mass spectrum 434 (M⁺¹), 436. Elemental analysiscalculated for C₂₁H₂₁N₃OSCl₂: C 58.07, H 4.87, N 9.67. Found: C 57.93, H4.71, N 9,43. Conversion to the hydrochloride salt using 1M HCl inCH₃OH, followed by recrystallization from isopropanol, gave acrystalline solid, m.p. 154-155° C.

Preparation 1 2-(4-Methylpiperazin-1-yl)-benzaldehyde

[0291] This compound was prepared using the methods of W. Nijhuis et al,Synthesis, 641-645 (1987) or J. Watthey et al, Journal of MedicinalChemistry, 26, 1116-1122 (1983).

[0292] In the same manner as the preparation of2-(4-methylpiperazin-1-yl)-benzaldehyde, the following analogs were alsoprepared:

4.6-Dibromo-2-(4-methylpiperazin-1-yl)-benzaldehyde

[0293] 72% yield. M.p. 92-93° C. Mass spectrum 362. ¹H-NMR (CDCl₃, 250MHz) δ10.12 (1H, s), 7.44 (1H, d), 7.16 (1H, d), 3.10 (4H, br s), 2.61(4H, s), 2.36 (3H, s).

6-Fluoro-2-(4-methylpiperazin-1-yl)-benzaldehyde

[0294] 69% yield. Light brown oil. Mass spectrum 223 (M⁺¹). ¹H-NMR(CDCl₃, 250 MHz) δ10.27 (1H,s), 7.45 (1H, m), 7.86 (1H, d), 6.75(1H,dd), 3.14 (4H,t), 2.62(4H, t), 2.37 (3H, s).

Preparation 2 2,4-Dibromo-6-fluoro-benzaldehyde.

[0295] In a flame-dried 250 mL round-bottomed flask equipped with anaddition funnel and magnetic stirrer, a mixture of diisopropylamine(4.82 mL, 34.66 mmol) in 100 mL of anhydrous THF was cooled to −78° C.and treated with 2.5N n-butyllithium (13.86 mL, 34.66 mmol) in THF,dropwise. After stirring for 10 minutes a mixture of3,5-dibromo-1-fluorobenzene (8.0 g, 31.51 mmol) in 16 mL of THF wasadded dropwise and stirring was continued for an additional 30 minutes.At this point, N,N-dimethylformamide (DMF) (2.68 mL, 34.66 mmol) wasadded dropwise and stirring continued another 10 minutes at −78° C. Thereaction was quenched with saturated aqueous ammonium chloride and thesolvent removed on a rotary evaporator. The residue was dissolved inether, washed with saturated brine and dried over calcium sulfate,filtered and concentrated to an oil, 7.36 g. Purification by flashchromatography using ethyl acetate-hexanes (1:99) gave the title productas a white solid.

[0296] M.p. 57-58° C. Mass spectrum 281 (M⁺¹), 283. ¹H-NMR (CDCl₃, 400MHz) δ10.29 (1H, s), 7.66 (1H, t), 7.33 (1H, dd). Elemental analysiscalculated for C₇H₃Br₂FO: C 29 82, H 1.07. Found: C 30.25, H 1.03.

Preparation 3 3-(4-Chlorobenzyl)-imidazolidine-2,4-dione

[0297] Under a nitrogen atmosphere in a flame-dried flask, with magneticstirring, the potassium salt of imidazolidine-2,4-dione (1.382 g, 10mmol) and 4-chlorobenzyl bromide (2.055 g, 10 mmol) were combined with15 mL of anhydrous N,N-dimethylformamide (DMF) and heated to 170-175° C.for 5 hours. The reaction was then cooled to room temperature and pouredover 50 mL of water to produce a waxy white precipitate.Recrystallization from ethyl acetate: hexanes produced the title productas a white crystalline solid, 0.775 g (34.5%).

[0298] M p. 162-163.5° C.(dec.). ¹H-NMR (DMSO-d₆) δ8.17 (1H, s), 7.34(4H, q), 4.51 (2H, s), 3.98 (2H, s), 3.35 (HOD, s).

[0299] In the same manner, the potassium salt of thiazolidine-2,4-dione(1.0 g, 6.45 mmol) was converted to3-(4-chlorobenzyl)-thiazolidine-2,4-dione, 0.97 g (62%).

[0300]¹H-NMR (CDCl₃, 250 MHz) δ7.32 (4H, sym m), 4.73 (2H, 2), 3.95 (2H,s).

Preparation 4 4-(3,4-Dichlorophenyl)-thiomorpholin-3one

[0301] Under a nitrogen atmosphere in a flame-dried flask, sodiumhydride (72 mg, 1.79 mmol, 60% oil dispersion) was washed with hexanesand then treated with 6 mL of anhydrous DMF, and cooled to 0° C.Thiomorpholin-3-one (200 mg, 1.71 mmol) was added in one portion withstirring. After gas evolution had stopped (ca. 30 min),4-iodo-1,2-dichlorobenzene (700 mg, 2.56 mmol) was added, followed after5 minutes by copper (1) bromide (490 mg, 3.42 mmol). After heating at75° C. overnight, the mixture was partitioned between ethyl acetate and1N lithium chloride, filtered through diatomaceous earth and combinedwith additional ethyl acetate washes of the diatomaceous earth filtercake. The organic layers were washed with additional 1N lithiumchloride, brine (saturated sodium chloride) and dried over calciumsulfate (CaSO4). Concentration in vacuo gave 363 mg of light brown oilwhich was flash chromatographed (30-50% ethyl acetate in hexanes) togive a white solid, 108 mg.

[0302]¹H-NMR (CDCl₃, 400 MHz) δ7.44 (1H, d), 7.37 (1H, s), 7.12 (1H,dd), 3.93 (2H, t). 3.43 (2H, s), 3.01 (2H, t).

Preparation 5 4-(4-Trifluoromethylphenyl)-thiomorpholin-3-one.

[0303] A mixture of thiomorpholin-3-one (500 mg, 4.27 mmol),4-trifluoromethyl-1-iodobenzene (1.25 mL, 8.5 mmol) and copper metal(814 mg, 12.8 mmol) was heated in a sealed glass tube at 185-200° C. for18 hours. The residue was then purified by flash chromatography to give260 mg of the title product as a white solid.

[0304] M.p. 85-87° C. Mass spectrum 262 (M⁺¹). ¹H-NMR (CDCl₃, 400 MHz)δ7.62 (2H, d), 7.37 (2H, d), 3.97 (2H, t), 3.43 (2H, s), 3.01 (2H, t).

[0305] In the same manner, 4-(3,4-dichlorophenyl)-thiomorpholin-3-onewas prepared using copper bronze (Aldrich Chemical Co., Milwaukee, Wis.)and heating in a round bottomed flask under nitrogen atmosphere at 170°in 37-46% isolated yield, m.p. 79-80° C.

Preparation 6 4-Benzylthiomorpholin-3-one

[0306] Under a nitrogen atmosphere in a flame-dried flask, sodiumhydride (4.65 g, 0.105 mol, 54% oil dispersion) was added to 150 mL ofanhydrous dimethylformamide (DMF), and the suspension was cooled to 0°C. Thiomorpholin-3-one (11.7 g, 0.1 mol) was added in portions over 30minutes with stirring. After gas evolution had stopped (ca. 30 minutes),benzyl chloride (12.1 g, 0.105 mol) in DMF (50 mL) was added andstirring was continued at room temperature overnight. The reaction wasthen warmed to 80° C. for 15 minutes and cooled. Water (250 mL) wasadded and the mixture was extracted with chloroform which was dried(MgSO₄) and concentrated in vacuo to an oil. The oil was triturated withethyl ether (Et₂O) and cooled by dry ice to give the product, 12.75 g asa solid, m.p. 60-62° C.

[0307] Recrystallization of 5 g from 100 mL of Et₂O gave 3.5 g of pureproduct, m.p. 62-63° C. along with a second crop of 0.75 g with m.p.62-63° C.

[0308] In the same manner, 4-(3,4-dichlorobenzyl)-thiomorpholin-3one wasprepared in 89% yield from 3,4-dichlorobenzyl bromide andthiomorpholin-3-one as a white solid.

[0309] M.p. 86-87° C. ¹H-NMR (CDCl₃, 400 MHz) δ7.38 (1H, d), 7.33 (1H,d), 7.10 (1H, dd), 4.56 (2H, s), 3.55-3.51 (2H, m), 3.37 (2H, s),2.81-2.76 (2H, m).

1. A compound of the formula

wherein R¹ is a group of the formula G¹, G², G³, G⁴, G⁵, G⁶ or G⁷depicted below,

a is zero to eight; each R¹³ is, independently, (C₁-C₄)alkyl or a(C₁-C₄)methylene bridge from one of the ring carbons of the piperazineor piperidine ring of G¹ or G², respectively, to the same or anotherring carbon or a ring nitrogen of the piperazine or piperidine ring ofG¹ or G², respectively, having an available bonding site, or to a ringcarbon of R⁶ having an available bonding site; E is oxygen, sulfur, SOor SO₂; X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C₁-C₆)alkyl,hydroxy, trifluoromethyl, (C₁-C₆)alkoxy, —SO_(t)(C₁-C₆)alkyl wherein tis zero one or two, —CO₂R¹⁰ or —CONR¹¹R¹²; Y is an optionallysubstituted (C₁-C₄) heteroalkyl bridge that, together with the atoms towhich it is attached, forms a five to seven membered heterocyclecontaining two to four heteroatoms selected from the group consisting of1,3-oxazolidin-4-on-5-yl, 1,3-oxazolidin-2,4-dion-5-yl,4,5-dihydro-1,2-oxazolidin-3-on-4-yl, 1,3-thiazolidin-4-on-5-yl,1,3-thiazolidin-2,4-dion-5-yl, 1,3-pyrazolidin-4-on-5-yl,1,3-imidazolidin-2,4-dion-5-yl, 1,2-pyrazolidin-3-on-4-yl,1,2-thiazolidin-1,1,3-trion-4-yl, 1,2-thiazolidin-3-on-4-yl,tetrahydro-1,2-oxazin-3-on-4-yl, tetrahydro-1,3-oxazin-4-on-5-yl,tetrahydro-1,3-oxazin-2,4-dion-5-yl, morpholin-3-on-2-yl,morpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-on-2-yl,tetrahydro-1,3-thiazin-4-on-5-yl, tetrahydro-1,3-thiazin-2,4-dion-5-yl,tetrahydro-1,2-thiazin-3-on-4-yl, thiomorpholin-3-on-2-yl,thiomorpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-thiazin-3-on-2-yl,hexahydro-1,2-diazin-3-on-4-yl, 4,5-dihydro-2H-pyridazin-3-on-4-yl,hexahydro-1,3-diazin-4-on-5-yl, hexahydro-1,3-diazin-2,4-dion-5-yl,piperazin-2-on-3-yl, piperazin-2,6-dion-3-yl,tetrahydro-1,3,4-thiadiazin-5-on-6-yl,5,6-dihydro-1,3,4-thiadiazin-5-on-6-yl, 1,3,4-oxadiazin-5-on-6-yl,5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl,tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-yl,tetrahydro-1,2,4-oxadiazin-5-on-6-yl,5,6-dihydro-1-2,4-oxadiazin-5-on-6-yl, 1,2,4-oxadiazin-3,5-dion-6-yl,1,2,4-trazin-6-on-5-yl, hexahydro-1,2-oxazepin-3-on-2-yl,hexahydro-1,3-oxazepin-4-on-5-yl, hexahydro-1,4-oxazepin-3-on-2-yl,hexahydro-1,4-oxazepin-3,5-dion-2-yl,hexahydro-1,4-oxazepin-3,5-dion-6-yl,2,3,5,6-tetrahydro-1-4-oxazepin-5,7-dion-6-yl,hexahydro-1,4-oxazepin-5-on-6-yl, hexahydro-1,3-oxazepin-2,4-dion-5-yl,hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro-1,4-thiazepin-3-on-2-yl,2,3,4,5-tetrahydro-1,4-thiazepin-3-on-2-yl,hexahydro-1,4-thiazepin-3,5-dion-2-yl,hexahydro-1,4-thiazepin-3,5-dion-6-yl,2,3,6,7-tetrahydro-1,4-thiazepin-5-on-6-yl,6,7-dihydro-1,4-thiazepin-5-on-6-yl,hexahydro-1,3-thiazepin-2,4-dion-5-yl, hexahydro-1,2-diazepin-3-on-4-yl,hexahydro-1,3-diazepin-2,4-dion-5-yl, hexahydro-1,4-diazepin-2-on-3-yl,hexahydro-1,4-diazepin-5-on-6-yl, hexahydro-1,4-diazepin-5,7-dion-6-yl,hexahydro-1,3,5-thiadiazepin-3-on-7-yl,4,5,6,7-tetrahydro-1-3,5-thiadiazepin-6-on-7-yl, and2,3,5,6-tetrahydro-1,2,4-triazepin-3,5-dion-7-yl; wherein thesubstituents on any of the carbon atoms capable of supporting anadditional bond, of said (C₁-C₄) heteroalkyl bridge, are chloro, fluoro,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl or cyano; wherein thesubstituents on any of the nitrogen atoms capable of supporting anadditional bond, of said (C₁-C₄) heteroalkyl bridge, are (C₁-C₈)alkyl ortrifluoromethyl; R² is hydrogen, (C₁-C₄)alkyl, phenyl or naphthyl,wherein said phenyl or naphthyl may optionally be substituted with oneor more substituents independently selected from chloro, fluoro, bromo,iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—SO_(k)(C₁-C₆)alkyl wherein k is zero, one or two; R³ is —(CH₂)_(m)B,wherein m is zero, one, two or three and B is hydrogen, phenyl, naphthylor a 5 or 6 membered heteroaryl group containing from one to fourheteroatoms in the ring, and wherein each of the foregoing phenyl,naphthyl and heteroaryl groups may optionally be substituted with one ormore substituents independently selected from chloro, fluoro, bromo,iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₈) alkoxy-(C₁-C₆)alkyl-,trifluoromethyl, trifluoromethoxy, cyano, hydroxy, —COOH and—SO_(n)(C₁-C₆)alkyl wherein n is zero, one or two; R⁶ is selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl optionally substitutedwith (C₁-C₆)alkoxy or one to three fluorine atoms, or [(C₁-C₄)alkyl]arylwherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_(q)—,wherein the heteroaryl moiety is selected from the group consisting ofpyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl andbenzisothiazolyl and q is zero, one, two, three or four, and whereinsaid aryl and heteroaryl moieties may optionally be substituted with oneor more substituents independently selected from the group consisting ofchloro, fluoro, bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,trifluoromethyl, cyano and —SO_(g)(C₁-C₆)alkyl, wherein g is zero, oneor two; R⁷ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, [(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl,naphthyl, or heteroaryl-(CH₂)_(r)—, wherein the heteroaryl moiety isselected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, —C(═O)—(C₁-C₆)alkyl, cyanoand —SO_(j)(C₁-C₆)alkyl, wherein j is zero, one or two; or R⁶ and R⁷taken together form a 2 to 4 carbon chain; R⁸ is hydrogen or(C₁-C₃)alkyl; R⁹ is hydrogen or (C₁-C₆)alkyl; or R⁶ and R⁹, togetherwith the nitrogen atom to which they are attached. form a 5 to 7membered heteroalkyl ring that may contain from zero to four heteroatomsselected from nitrogen, sulfur and oxygen; and p is one, two, or three;each of R¹⁰, R¹¹ and R¹² is selected, independently, from the radicalsset forth in the definition of R²; or R¹¹ and R¹², together with thenitrogen to which they are attached, form a 5 to 7 membered heteroalkylring that may contain from zero to four heteroatoms selected fromnitrogen, sulfur and oxygen; and the broken lines indicate optionaldouble bonds, with the proviso that when the broken line in G² is adouble bond that R⁸ is absent; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1, wherein R¹ is

R⁶ is methyl and R² is hydrogen.
 3. A compound according to claim 1wherein Y together, with the atoms to which it is attached, forms anoptionally substituted five to seven membered heterocycle selected from1,3-thiazolidin-2,4-dion-5-yl, 1,3-imidazolidin-2,4-dion-5-yl,thiomorpholin-3-on-2-yl or morpholin-3-on-2-yl.
 4. A compound accordingto claim 2, wherein Y together, with the atoms to which it is attached,forms thiomorpholin-3-on-2-yl.
 5. A compound according to claim 1,wherein R³ is optionally substituted phenyl or —(CH₂)-optionallysubstituted phenyl.
 6. A compound according to claim 2, wherein R³ isoptionally substituted phenyl or —(CH₂)-optionally substituted phenyl.7. A compound according to claim 3, wherein R³ is optionally substitutedphenyl or —(CH₂)-optionally substituted phenyl.
 8. A compound accordingto claim 4, wherein R³ is optionally substituted phenyl or—(CH₂)-optionally substituted phenyl.
 9. A compound according to claim1, wherein said compound is selected from the group consisting of:3-(4-chlorobenzyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-imidazolidine-2,4-dione;3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-imidazolidine-2,4-dione;3-(4-chlorobenzyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dione;4-benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-dichlorobenzyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dione;3-(4-trifluoromethylphenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dione;2-[2-(4-methylpiperazin-1-yl)-benzylidene]-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-morpholin-3-one;4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzyl]-thiomorpholin-3-one;4-methyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;and4-(3,4-dichlorophenyl)-2-(2-piperazin-1-ylbenzylidene)-thiomorpholin-3-one.and the pharmaceutically acceptable salts of such compounds.
 10. Acompound of the formula

wherein R¹ is a group of the formula G¹, G², G³, G⁴, G⁵, G⁶ or G⁷depicted below,

E is oxygen, sulfur, SO or SO₂; X is hydrogen, chloro, fluoro, bromo,iodo, cyano, (C₁-C₆)alkyl, hydroxy, trifluoromethyl, (C₁-C₈)alkoxy,—SO_(t)(C₁-C₆)alkyl wherein t is zero one or two, —CO₂R¹⁰ or —CONR¹¹R¹²;Y is an optionally substituted (C₁-C₄) heteroalkyl bridge that, togetherwith the atoms to which it is attached, forms a five to seven memberedheterocycle containing two to four heteroatoms selected from the groupconsisting of 1,3-oxazolidin-4-on-5-yl, 1,3-oxazolidin-2,4-dion-5-yl,4,5-dhydro-1,2-oxazolidin-3-on-4-yl, 1,3-thiazolidin-4-on-5-yl,1,3-thiazolidin-2,4-dion-5-yl, 1,3-imidazolidin-4-on-5-yl,1,3-imidazolidin-2,4-dion-5-yl, 1,2-pyrazolidin-3-on-4-yl,1,2-thiazolidin-1,1,3-trion-4-yl, 1,2-thiazolidin-3-on-4-yl,tetrahydro-1,2-oxazin-3-on-4-yl, tetrahydro-1,3-oxazin-4-on-5-yl,tetrahydro-1,3-oxazin-2,4-dion-5-yl, morpholin-3-on-2-yl,morpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-on-2-yl,tetrahydro-1,3-thiazin-4-on-5-yl, tetrahydro-1,3-thiazin-2,4-dion-5-yl,tetrahydro-1,2-thiazin-3-on-4-yl, thiomorpholin-3-on-2-yl,thiomorpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-thiazin-3-on-2-yl,hexahydro-1,2-diazin-3-on-4-yl, 4,5-dihydro-2H-pyridazin-3-on-4-yl,hexahydro-1,3-diazin-4-on-5-yl, hexahydro-1,3-diazin-2,4-dion-5-yl,piperazin-2-on-3-yl, piperazin-2,6-dion-3-yl,tetrahydro-1,3,4-thiadiazin-5-on-6-yl,5,6-dihydro-1,3,4-thiadiazin-5-on-6-yl, 1,3,4-oxadiazin-5-on-6-yl,5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl,tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-yl,tetrahydro-1,2,4-oxadiazin-5-on-6-yl,5,6-dihydro-1-2,4-oxadiazin-5-on-6yl, 1,2,4-oxadiazin-3,5-dion-6-yl,1,2,4-trazin-6-on-5-yl, hexahydro-1,2-oxazepin-3-on-2-yl,hexahydro-1,3-oxazepin-4-on-5-yl, hexahydro-1,4-oxazepin-3-on-2-yl,hexahydro-1,4-oxazepin-3,5-dion-2-yl,hexahydro-1,4-oxazepin-3,5-dion-6-yl,2,3,5,6-tetrahydro-1-4-oxazepin-5,7-dion-6-yl,hexahydro-1,4-oxazepin-5-on-6-yl, hexahydro-1,3-oxazepin-2,4-dion-5-yl,hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro-1,4-thiazepin-3-on-2-yl,2,3,4,5-tetrahydro-1,4-thiazepin-3-on-2-yl,hexahydro-1,4-thiazepin-3,5-dion-2-yl,hexahydro-1,4-thiazepin-3,5-dion-6-yl,2,3,6,7-tetrahydro-1,4-thiazepin-5-on-6-yl,6,7-dihydro-1,4-thiazepin-5-on-6-yl,hexahydro-1,3-thiazepin-2,4-dion-5-yl, hexahydro-1,2-diazepin-3-on-4-yl,hexahydro-1,3-diazepin-2,4-dion-5-yl, hexahydro-1,4-diazepin-2-on-3-yl,hexahydro-1,4-diazepin-5-on-6-yl, hexahydro-1,4-diazepin-5,7-dion-6-yl,hexahydro-1,3,5-thiadiazepin-2,6-dion-7-yl,4,5,6,7-tetrahydro-1-3,5-thiadiazepin-6-on-7-yl,and 2,3,5,6-tetrahydro-1,2,4-triazepin-3,5-dion-7-yl; wherein thesubstituents on any of the carbon atoms capable of supporting anadditional bond, of said (C₁-C₄) heteroalkyl bridge. are chloro, fluoro,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl or cyano; wherein thesubstituents on any of the nitrogen atoms capable of supporting anadditional bond, of said (C₁-C₄) heteroalkyl bridge, are (C₁-C₆)alkyl ortrifluoromethyl; R² is hydrogen, (C₁-C₄)alkyl, phenyl or naphthyl,wherein said phenyl or naphthyl may optionally be substituted with oneor more substituents independently selected from chloro, fluoro, bromo,iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano and—SO_(k)(C₁-C₆)alkyl wherein k is zero, one or two; R³ is —(CH₂)_(m)B,wherein m is zero, one, two or three and B is hydrogen, phenyl, naphthylor a 5 or 6 membered heteroaryl group containing from one to four heteroatoms in the ring, and wherein each of the foregoing phenyl, naphthyland heteroaryl groups may optionally be substituted with one or moresubstituents independently selected from chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkyl-,trifluoromethyl, trifluoromethoxy, cyano, hydroxy, —COOH and—SO_(n)(C₁-C₆)alkyl wherein n is zero, one or two; R⁶ is selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl optionally substitutedwith (C₁-C₆)alkoxy or one to three fluorine atoms, or [(C₁-C₄)alkyl]arylwherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_(q)—,wherein the heteroaryl moiety is selected from the group consisting ofpyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl andbenzisothiazolyl and q is zero, one, two, three or four, and whereinsaid aryl and heteroaryl moieties may optionally be substituted with oneor more substituents independently selected from the group consisting ofchloro, fluoro, bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,trifluoromethyl, cyano and —SO_(g)(C₁-C₆)alkyl, wherein g is zero, oneor two; R⁷ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, [(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl,naphthyl, or heteroaryl-(CH₂)_(r)—, wherein the heteroaryl moiety isselected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one,two, three or four, and wherein said aryl and heteroaryl moieties mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of chloro, fluoro, bromo, iodo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, —C(═O)—(C₁-C₆)alkyl, cyanoand —SO,(C₁-C₆)alkyl, wherein j is zero, one or two; or R⁶ and R⁷ takentogether form a 2 to 4 carbon chain; R⁸ is hydrogen or (C₁-C₃)alkyl; R⁹is hydrogen or (C₁-C₆)alkyl; or R⁶ and R⁹, together with the nitrogenatom to which they are attached, form a 5 to 7 membered heteroalkyl ringthat may contain from one to four heteroatoms selected from nitrogen,sulfur and oxygen; and p is one, two, or three; each of R¹⁰, R¹¹ and R¹²is selected, independently, from the radicals set forth in thedefinition of R²; or R¹¹ and R¹², together with the nitrogen to whichthey are attached, form a 5 to 7 membered heteroalkyl ring that maycontain from zero to four heteroatoms selected from nitrogen, sulfur andoxygen; and the broken lines indicate optional double bonds, with theproviso that when the broken line in G² is a double bond that R⁸ isabsent.
 11. A compound according to claim 10, wherein said compound isselected from the group consisting of:4-benzyl-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}-thiomorpholin-3-one;4-(3,4-dichlorobenzyl)-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}-thiomorpholin-3one;2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}-4-(4-trifluoromethylphenyl)-thiomorpholin-3-one;2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}-thiomorpholin-3-one;4-(3,4-dichlorophenyl)-2-{[2-fluoro-6-(4-methylpiperazin-1-yl)-hydroxymethyl}-thiomorpholin-3-one;4-(3,4-dichlorophenyl)-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]-methyl}-morpholin-3-one;2-{[2,4-dibromo-6-(4-methylpiperazin-1-yl)-phenyl]-hydroxymethyl}-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;4-(3,4-dichlorophenyl)-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]-methyl}-thiomorpholin-3-one;4-Benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,1-dioxothiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[3-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-5-trifluoromethyl-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-{2-[4-(2-methoxyethyl)piperazin-1-yl]-benzylidene}-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(4-isopropylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(4-ethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(4-Chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3-Chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;2-[2-Chloro-6-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-4-trifluoromethyl-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-oxo-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-(5-fluoro-2-piperazin-1-yl-benzylidene)-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[3,6-difluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-Phenyl-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;2-[5-Fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-4-phenyl-thiomorpholin-3-one;4-Benzo[1,3]dioxol-5-yl-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;2-[2-(4-tert-Butylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;3-(3,4-Dichlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidin-4-one;3-[4-(3,4-Dichlorophenyl)-3-oxo-thiomorpholin-2-ylidenemethyl]-6-dimethylamino-2-(4-methylpiperazin-1-yl)-benzonitrile;5-[2-(4-Methylpiperazin-1-yl)-benzylidene]-2-phenylthiazolidin-4-one;4-(3,4-Dichlorophenyl)-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[5-methyl-2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;2-[4-Chloro-2-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;4-(3,4-Difluorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(2,4-Difluorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;2-[4-Bromo-2-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(1-methylpyrrolidin-2-ylmethoxy)-benzylidene]-thiomorpholin-3-one;4-(3,5-Dichlorophenyl)-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Difluorophenyl)-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(octahydropyrido[1,2-a]pyrazin-2-yl)-benzylidene]-thiomorpholin-3-one;2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-pyridin-3-yl-thiomorpholin-3-one;2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,4-difluorophenyl)-thiomorpholin-3-one;2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,5-dichlorophenyl)-thiomorpholin-3-one;4-(3,4-Difluorophenyl)-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,5-Dichlorophenyl)-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(3-methylaminopyrrolidin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Difluorophenyl)-2-[2-(2,4,5-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-Benzo[1,3]dioxol-5-yl-2-[2-(4-cyclopropylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;2-[2-(3,5-Dimethylpiperazin-1-yl)-benzylidene]-4-(4-fluorophenyl)-thiomorpholin-3-one;4-Benzo[1,3]dioxol-5-yl-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;2-[2-(3,5-Dimethylpiperazin-1-yl)-benzylidene]-4-phenylthiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-1-yl)-benzylidene]-thiomorpholin-3one;4-(3,4-Dichlorophenyl)-2-[2-(3-dimethylaminopyrrolidin-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(4-methyl-[1,4]diazepan-1-yl)-benzylidene]-thiomorpholin-3-one;4-(3,4-Dichlorophenyl)-2-[2-(2,4,6-trimethylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one;and2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)-thiomorpholin-3-one.12. A pharmaceutical composition for treating or preventing a disorderor condition selected from hypertension, depression, generalized anxietydisorder, phobias, posttraumatic stress syndrome, avoidant personalitydisorder, premature ejaculation, eating disorders, obesity, chemicaldependencies, cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders,Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia,gastrointestinal tract disorders, negative symptoms of schizophrenia,premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence,Tourette syndrome, trichotillomania, kleptomania, male impotence,cancer, chronic paroxysmal hemicrania and headache in a mammal,comprising an amount of a compound according to claim 1 that iseffective in treating or preventing such disorder or condition and apharmaceutically acceptable carrier.
 13. A pharmaceutical compositionfor treating or preventing a disorder or condition that can be treatedor prevented by enhancing serotonergic neurotransmission in a mammal,comprising an amount of a compound according to claim 1 that iseffective in treating or preventing such disorder or condition and apharmaceutically acceptable carrier.
 14. A method for treating orpreventing a disorder or condition selected from hypertension,depression, generalized anxiety disorder, phobias, posttraumatic stresssyndrome, avoidant personality disorder, premature ejaculation, eatingdisorders, obesity, chemical dependencies, cluster headache, migraine,pain, Alzheimer's disease, obsessive-compulsive disorder, panicdisorder, memory disorders, Parkinson's diseases, endocrine disorders,vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negativesymptoms of schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome,stress incontinence, Tourette syndrome, trichotillomania, kleptomania,male impotence, cancer, chronic paroxysmal hemicrania and headache in amammal, comprising administering to a mammal in need of such treatmentor prevention an amount of a compound according to claim 1 that iseffective in treating or preventing such disorder or condition.
 15. Amethod for treating or preventing a disorder or condition that can betreated or prevented by enhancing serotonergic neurotransmission in amammal, comprising administering to a mammal in need of such treatmentor prevention an amount of a compound according to claim 1 that iseffective in treating or preventing such disorder or condition.
 16. Apharmaceutical composition for treating or preventing a disorder orcondition selected from hypertension, depression, generalized anxietydisorder, phobias, posttraumatic stress syndrome, avoidant personalitydisorder, premature ejaculation, eating disorders, obesity, chemicaldependencies, cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders,Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia,gastrointestinal tract disorders, negative symptoms of schizophrenia,premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence,Tourette syndrome, trichotillomania, kleptomania, male impotence,cancer, chronic paroxysmal hemicrania and headache in a mammal,comprising a serotonin receptor antagonizing or agonizing effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 17. A pharmaceutical composition for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, comprising aserotonin receptor antagonizing or agonizing effective amount of acompound of according to claim 1 and a pharmaceutically acceptablecarrier.
 18. A method for treating or preventing a disorder or conditionselected from hypertension, depression, generalized anxiety disorder,phobias, posttraumatic stress syndrome, avoidant personality disorder,sexual dysfunction, eating disorders, obesity, chemical dependencies,cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders,Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia,gastrointestinal tract disorders, negative symptoms of schizophrenia,premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence,Tourette syndrome, trichotillomania, kleptomania, male impotence,cancer, chronic paroxysmal hemicrania and headache in a mammal,comprising administering to a mammal requiring such treatment orprevention a serotonin receptor antagonizing or agonizing effectiveamount of a compound according to claim
 1. 19. A method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, comprisingadministering to a mammal requiring such treatment or prevention aserotonin receptor antagonizing or agonizing effective amount of acompound according to claim
 1. 20. A pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by enhancing serotonergic neurotransmission in a mammal,comprising: a) a pharmaceutically acceptable carrier; b) a compound ofaccording to claim 1; and c) a 5-HT re-uptake inhibitor or apharmaceutically acceptable salt thereof; wherein the amount of theactive compounds are such that the combination is effective in treatingor preventing such disorder or condition.
 21. A method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, comprisingadministering to a mammal requiring such treatment or prevention: a) acompound according to claim 1; and b) a 5-HT re-uptake inhibitor or apharmaceutically acceptable salt thereof; wherein the amounts of theactive compounds are such that the combination is effective in treatingor preventing such disorder or condition.
 22. A pharmaceuticalcomposition according to claim 20, wherein the 5-HT re-uptake inhibitoris sertraline or a pharmaceutically acceptable salt thereof.
 23. Amethod according to claim 21, wherein the 5-HT re-uptake inhibitor issertraline or a pharmaceutically acceptable salt thereof.
 24. A methodfor treating or preventing a disorder or condition selected fromhypertension, depression, generalized anxiety disorder, phobias,posttraumatic stress syndrome, avoidant personality disorder, sexualdysfunction, eating disorders, obesity, chemical dependencies, clusterheadache, migraine, pain, Alzheimer's disease, obsessive-compulsivedisorder, panic disorder, memory disorders, Parkinson's diseases,endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinaltract disorders, negative symptoms of schizophrenia, premenstrualsyndrome, Fibromyalgia Syndrome, stress incontinence, Tourette syndrome,trichotillomania, kleptomania, male impotence, cancer, chronicparoxysmal hemicrania and headache in a mammal, comprising administeringto a mammal requiring such treatment or prevention: a) a compoundaccording to claim 1; and b) a 5-HT re-uptake inhibitor or apharmaceutically acceptable salt thereof; wherein the amounts of theactive compounds are such that the combination is effective in treatingor preventing such disorder or condition.
 25. A method for treating orpreventing a disorder or condition that can be treated or prevented byenhancing serotonergic neurotransmission in a mammal, comprisingadministering to said mammal requiring such treatment or prevention: a)a 5-HT_(1A) antagonist or a pharmaceutically acceptable salt thereof;and b) a 5-HT_(1D) antagonist of formula I or a pharmaceuticallyacceptable salt thereof; wherein the amounts of the active compounds aresuch that the combination is effective in treating or preventing suchdisorder or condition.
 26. A method for treating or preventing adisorder or condition selected from hypertension, depression,generalized anxiety disorder, phobias, posttraumatic stress syndrome,avoidant personality disorder, sexual dysfunction, eating disorders,obesity, chemical dependencies, cluster headache, migraine, pain,Alzheimer's disease, obsessive-compulsive disorder, panic disorder,memory disorders, Parkinson's diseases, endocrine disorders, vasospasm,cerebellar ataxia, gastrointestinal tract disorders, negative symptomsof schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome, stressincontinence, Tourette syndrome, trichotillomania, kleptomania, maleimpotence, cancer, chronic paroxysmal hemicrania and headache in amammal, comprising administering to a mammal requiring such treatment orprevention: a) a 5-HT_(1A) antagonist or a pharmaceutically acceptablesalt thereof; and b) a 5-HT_(1D) antagonist of formula I or apharmaceutically acceptable salt thereof; wherein the amounts of theactive compounds are such that the combination is effective in treatingor preventing such disorder or condition.
 27. A pharmaceuticalcomposition for treating or preventing a disorder or condition that canbe treated or prevented by enhancing serotonergic neurotransmission in amammal, comprising: a) a 5-HT_(1A) antagonist or a pharmaceuticallyacceptable salt thereof; and b) a 5-HT_(1D) antagonist of formula I or apharmaceutically acceptable salt thereof; wherein the amounts of theactive compounds are such that the combination is effective in treatingor preventing such disorder or condition.
 28. A pharmaceuticalcomposition for treating or preventing a disorder or condition selectedfrom hypertension, depression, generalized anxiety disorder, phobias,posttraumatic stress syndrome, avoidant personality disorder, sexualdysfunction, eating disorders, obesity, chemical dependencies, clusterheadache, migraine, pain, Alzheimer's disease, obsessive-compulsivedisorder, panic disorder, memory disorders, Parkinson's diseases,endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinaltract disorders, negative symptoms of schizophrenia, premenstrualsyndrome, Fibromyalgia Syndrome, stress incontinence, Tourette syndrome,trichotillomania, kleptomania, male impotence, cancer, chronicparoxysmal hemicrania and headache in a mammal, comprising: a) a5-HT_(1A) antagonist or a pharmaceutically acceptable salt thereof; andb) a 5-HT_(1D) antagonist of formula I or a pharmaceutically acceptablesalt thereof; wherein the amounts of the active compounds are such thatthe combination is effective in treating or preventing such disorder orcondition.